@article {387, title = {A multi-omics data analysis workflow packaged as a FAIR Digital Object}, journal = {GigaScience}, volume = {13}, year = {2024}, month = {01}, pages = {giad115}, abstract = {

Applying good data management and FAIR (Findable, Accessible, Interoperable, and Reusable) data principles in research projects can help disentangle knowledge discovery, study result reproducibility, and data reuse in future studies. Based on the concepts of the original FAIR principles for research data, FAIR principles for research software were recently proposed. FAIR Digital Objects enable discovery and reuse of Research Objects, including computational workflows for both humans and machines. Practical examples can help promote the adoption of FAIR practices for computational workflows in the research community. We developed a multi-omics data analysis workflow implementing FAIR practices to share it as a FAIR Digital Object.We conducted a case study investigating shared patterns between multi-omics data and childhood externalizing behavior. The analysis workflow was implemented as a modular pipeline in the workflow manager Nextflow, including containers with software dependencies. We adhered to software development practices like version control, documentation, and licensing. Finally, the workflow was described with rich semantic metadata, packaged as a Research Object Crate, and shared via WorkflowHub.Along with the packaged multi-omics data analysis workflow, we share our experiences adopting various FAIR practices and creating a FAIR Digital Object. We hope our experiences can help other researchers who develop omics data analysis workflows to turn FAIR principles into practice.

}, issn = {2047-217X}, doi = {10.1093/gigascience/giad115}, url = {https://doi.org/10.1093/gigascience/giad115}, author = {Niehues, Anna and de~Visser, Casper and Hagenbeek, Fiona A and Kulkarni, Purva and Pool, Ren{\'e} and Karu, Naama and Kindt, Alida S D and Singh, Gurnoor and Vermeiren, Robert R J M and Boomsma, Dorret I and van~Dongen, Jenny and {\textquoteright}t~Hoen, Peter A C and van~Gool, Alain J} } @article {382, title = {Beyond the global brain differences: Intra-individual variability differences in 1q21.1 distal and 15q11.2 BP1-BP2 deletion carriers}, journal = {Biological Psychiatry}, year = {2023}, abstract = {

BACKGROUND: The 1q21.1 distal and 15q11.2 BP1-BP2 CNVs exhibit regional and global brain differences compared to non-carriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intra-individual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n=30) and duplication (n=27), and 15q11.2 BP1-BP2 deletion (n=170) and duplication (n=243) carriers and matched non-carriers (n=2,350). Regional intra-deviation (RID) scores i.e., the standardized difference between an individual\&$\#$39;s regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate and temporal pole differed less, and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex and temporal pole differed less, and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSION: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 CNVs. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 CNVs, with the potential to increase our understanding of mechanisms involved in altered neurodevelopment.

}, keywords = {15q11.2 BP1-BP2, 1q21.1 distal, brain structure, copy number variants, intra-individual variability, magnetic resonance imaging}, doi = {10.1016/j.biopsych.2023.08.018}, author = {Boen, Rune and Kaufmann, Tobias and van der Meer, Dennis and Frei, Oleksandr and Agartz, Ingrid and Ames, David and Andersson, Micael and Armstrong, Nicola J and Artiges, Eric and Atkins, Joshua R and Bauer, Jochen and Benedetti, Francesco and Boomsma, Dorret I and Brodaty, Henry and Brosch, Katharina and Buckner, Randy L and Cairns, Murray J and Calhoun, Vince and Caspers, Svenja and Cichon, Sven and Corvin, Aiden P and Facorro, Benedicto Crespo and Dannlowski, Udo and David, Friederike S and de Geus, Eco J C and de Zubicaray, Greig I and Desrivi{\`e}res, Sylvane and Doherty, Joanne L and Donohoe, Gary and Ehrlich, Stefan and Eising, Else and Espeseth, Thomas and Fisher, Simon E and Forstner, Andreas J and Uy{\`a}, Lidia Fortaner and Frouin, Vincent and Fukunaga, Masaki and Ge, Tian and Glahn, David C and Goltermann, Janik and Grabe, Hans J and Green, Melissa J and Groenewold, Nynke A and Grotegerd, Dominik and Hahn, Tim and Hashimoto, Ryota and Hehir-Kwa, Jayne Y and Henskens, Frans A and Holmes, Avram J and Haberg, Asta K and Haavik, Jan and Jacquemont, S{\'e}bastien and Jansen, Andreas and Jockwitz, Christiane and J{\"o}nsson, Erik G and Kikuchi, Masataka and Kircher, Tilo and Kumar, Kuldeep and Le Hellard, Stephanie and Leu, Costin and Linden, David E and Liu, Jingyu and Loughnan, Robert and Mather, Karen A and McMahon, Katie L and McRae, Allan F and Medland, Sarah E and Meinert, Susanne and Moreau, Clara A and Morris, Derek W and Mowry, Bryan J and M{\"u}hleisen, Thomas W and Nenadi{\'c}, Igor and N{\"o}then, Markus M and Nyberg, Lars and Owen, Michael J and Paolini, Marco and Paus, Tomas and Pausova, Zdenka and Persson, Karin and Quid{\'e}, Yann and Marques, Tiago Reis and Sachdev, Perminder S and Sando, Sigrid B and Schall, Ulrich and Scott, Rodney J and Selb{\ae}k, Geir and Shumskaya, Elena and Silva, Ana I and Sisodiya, Sanjay M and Stein, Frederike and Stein, Dan J and Straube, Benjamin and Streit, Fabian and Strike, Lachlan T and Teumer, Alexander and Teutenberg, Lea and Thalamuthu, Anbupalam and Tooney, Paul A and Tordesillas-Guti{\'e}rrez, Diana and Trollor, Julian N and Ent, Dennis van {\textquoteright}t and van den Bree, Marianne B M and van Haren, Neeltje E M and Vazquez-Bourgon, Javier and V{\"o}lzke, Henry and Wen, Wei and Wittfeld, Katharina and Ching, Christopher R K and Westlye, Lars T and Thompson, Paul M and Bearden, Carrie E and Selmer, Kaja K and Aln{\ae}s, Dag and Andreassen, Ole A and Sonderby, Ida E} } @article {385, title = {Genetics and epigenetics of human aggression}, journal = {Handbook of Clinical Neurology, Brain and Crime}, volume = {197}, year = {2023}, pages = {13{\textendash}44}, abstract = {

There is substantial variation between humans in aggressive behavior, with its biological etiology and molecular genetic basis mostly unknown. This review chapter offers an overview of genomic and omics studies revealing the genetic contribution to aggression and first insights into associations with epigenetic and other omics (e.g., metabolomics) profiles. We allowed for a broad phenotype definition including studies on {\textquoteleft}{\textquoteleft}aggression,\&$\#$39;\&$\#$39; {\textquoteleft}{\textquoteleft}aggressive behavior,\&$\#$39;\&$\#$39; or {\textquoteleft}{\textquoteleft}aggression-related traits,\&$\#$39;\&$\#$39; {\textquoteleft}{\textquoteleft}antisocial behavior,\&$\#$39;\&$\#$39; {\textquoteleft}{\textquoteleft}conduct disorder,\&$\#$39;\&$\#$39; and {\textquoteleft}{\textquoteleft}oppositional defiant disorder.\&$\#$39;\&$\#$39; Heritability estimates based on family and twin studies in children and adults of this broadly defined phenotype of aggression are around 50\%, with relatively small fluctuations around this estimate. Next, we review the genome-wide association studies (GWAS) which search for associations with alleles and also allow for gene-based tests and epigenome-wide association studies (EWAS) which seek to identify associations with differently methylated regions across the genome. Both GWAS and EWAS allow for construction of Polygenic and DNA methylation scores at an individual level. Currently, these predict a small percentage of variance in aggression. We expect that increases in sample size will lead to additional discoveries in GWAS and EWAS, and that multiomics approaches will lead to a more comprehensive understanding of the molecular underpinnings of aggression.

}, keywords = {Epigenome-wide association studies, Epigenomics, genome-wide association studies, Genomics, heritability, Human aggression}, doi = {10.1016/B978-0-12-821375-9.00005-0}, author = {Odintsova, Veronika V and Hagenbeek, Fiona A and Van der Laan, Camiel M and van de Weijer, Steve and Boomsma, Dorret I} } @article {386, title = {Genome-wide analyses of vocabulary size in infancy and toddlerhood: associations with ADHD, literacy and cognition-related traits}, journal = {Biological Psychiatry}, year = {2023}, abstract = {
BACKGROUND. The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes and neurodevelopmental conditions, including Attention-Deficit/Hyperactivity Disorder (ADHD).
METHODS. We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 European descent children. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h2) and genetic correlations (rg), and modelled underlying factor structures with multivariate models.
RESULTS. Early-life vocabulary size was modestly heritable (SNP-h2: 0.08(SE=0.01) to 0.24(SE=0.03)). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg=0.07(SE=0.10)), although each measure was moderately related to toddler expressive vocabulary (rg=0.69(SE=0.14) and rg=0.67(SE=0.16), respectively), suggesting a multi-factorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g. spelling: rg=0.58(SE=0.20) and rg=0.79(SE=0.25), respectively), underlining genetic similarity. However, genetic association of early-life vocabulary with educational attainment and intelligence emerged in toddlerhood only (e.g. receptive vocabulary and intelligence: rg=0.36(SE=0.12)). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg=0.23(SE=0.08)). Multivariate genetic models in the ALSPAC cohort confirmed this finding for ADHD symptoms (rg=0.54(SE=0.26)), but showed that the association effect reversed for toddler receptive vocabulary (rg=-0.74(SE=0.23)), highlighting developmental heterogeneity.
CONCLUSIONS. The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy and cognition-related traits.

}, doi = {10.1016/j.biopsych.2023.11.025}, author = {Verhoef, Ellen and Allegrini, Andrea G and Jansen, Philip R and Lange, Katherine and Wang, Carol A and Morgan, Angela T and Ahluwalia, Tarunveer S and Symeonides, Christos and Eising, Else and Franken, Marie-Christine and Hypponen, Elina and Mansell, Toby and Olislagers, Mitchell and Omerovic, Emina and Rimfeld, Kaili and Schlag, Fenja and Selzam, Saskia and Shapland, Chin Yang and Tiemeier, Henning and Whitehouse, Andrew J O and Saffery, Richard and B{\o}nnelykke, Klaus and Reilly, Sheena and Pennell, Craig E and Wake, Melissa and Cecil, Charlotte A M and Plomin, Robert and Fisher, Simon E and St Pourcain, Beate and Andreassen, Ole A and Bartels, Meike and Boomsma, Dorret and Dale, Philip S and Ehli, Erik and Fernandez-Orth, Dietmar and Guxens, M{\`o}nica and Hakulinen, Christian and Harris, Kathleen Mullan and Haworth, Simon and de Hoyos, Luc{\'\i}a and Jaddoe, Vincent and Keltikangas-J{\"a}rvinen, Liisa and Lehtim{\"a}ki, Terho and Middeldorp, Christel and Min, Josine L and Mishra, Pashupati P and Nj{\o}lstad, P\aal Rasmus and Sunyer, Jordi and Tate, Ashley E and Timpson, Nicholas and van der Laan, Camiel and Vrijheid, Martine and Vuoksimaa, Eero and Whipp, Alyce and Ystrom, Eivind} } @article {370, title = {Integrative multi-omics analysis of childhood aggressive behavior}, journal = {Behavior Genetics}, volume = {53}, year = {2023}, pages = {101{\textendash}117}, abstract = {

This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42\%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 27

}, keywords = {childhood aggression, DNA methylation, Genetic nurturing, metabolomics, Multi-omics, polygenic scores}, doi = {10.1007/s10519-022-10126-7}, author = {Hagenbeek, Fiona A and van Dongen, Jenny and Pool, Ren{\'e} and Roetman, Peter J and Harms, Amy C and Hottenga, Jouke Jan and Kluft, Cornelis and Colins, Olivier F and van Beijsterveldt, Catharina E M and Fanos, Vassilios and Ehli, Erik A and Hankemeier, Thomas and Vermeiren, Robert R J M and Bartels, Meike and D{\'e}jean, S{\'e}bastien and Boomsma, Dorret I} } @article {384, title = {Integrative multi-omics analysis of genomic, epigenomic, and metabolomics data leads to new insights for Attention-Deficit/Hyperactivity Disorder}, journal = {American Journal of Medical Genetics Part B: Neuropsychiatric Genetics}, year = {2023}, pages = {e32955}, abstract = {

The evolving field of multi-omics combines data and provides methods for simultaneous analysis across several omics levels. Here, we integrated genomics (transmitted and non-transmitted polygenic scores [PGSs]), epigenomics, and metabolomics data in a multi-omics framework to identify biomarkers for Attention-Deficit/Hyperactivity Disorder (ADHD) and investigated the connections among the three omics levels. We first trained single- and next multi-omics models to differentiate between cases and controls in 596 twins (cases = 14.8\%) from the Netherlands Twin Register (NTR) demonstrating reasonable in-sample prediction through cross-validation. The multi-omics model selected 30 PGSs, 143 CpGs, and 90 metabolites. We confirmed previous associations of ADHD with glucocorticoid exposure and the transmembrane protein family TMEM, show that the DNA methylation of the MAD1L1 gene associated with ADHD has a relation with parental smoking behavior, and present novel findings including associations between indirect genetic effects and CpGs of the STAP2 gene. However, out-of-sample prediction in NTR participants (N = 25

}, keywords = {ADHD, DNA methylation, genetic nurture, metabolites, Multi-omics, polygenic scores}, doi = {10.1002/ajmg.b.32955}, author = {Hubers, Nikki and Hagenbeek, Fiona A and Pool, Ren{\'e} and D{\'e}jean, S{\'e}bastien and Harms, Amy C and Roetman, Peter J and van Beijsterveldt, Catharina E M and Fanos, Vassilios and Ehli, Erik A and Vermeiren, Robert R J M and Bartels, Meike and Hottenga, Jouke Jan and Hankemeier, Thomas and van Dongen, Jenny and Boomsma, Dorret I} } @unpublished {383, title = {Longitudinal multi-omics study reveals common etiology underlying association between plasma proteome and BMI trajectories in adolescent and young adult twins}, journal = { medRxiv}, year = {2023}, abstract = {

Background: The influence of genetics and environment on the association of the plasma proteome with body mass index (BMI) and changes in BMI remain underexplored, and the links to other omics in these associations remain to be investigated. We characterized protein-BMI trajectory associations in adolescents and adults and how these connect to other omics layers. Methods: Our study included two cohorts of longitudinally followed twins: FinnTwin12 (N=651) and the Netherlands Twin Register (NTR) (N=665). Follow-up comprised four BMI measurements over approximately 6 (NTR: 23-27 years old) to 10 years (FinnTwin12: 12-22 years old), with omics data collected at the last BMI measurement. BMI changes were calculated using latent growth curve models. Mixed-effects models were used to quantify the associations between the abundance of 439 plasma proteins with BMI at blood sampling and changes in BMI. The sources of genetic and environmental variation underlying the protein abundances were quantified using twin models, as were the associations of proteins with BMI and BMI changes. In NTR, we investigated the association of gene expression of genes encoding proteins identified in FinnTwin12 with BMI and changes in BMI. We linked identified proteins and their coding genes to plasma metabolites and polygenic risk scores (PRS) using mixed-effect models and correlation networks. Results: We identified 66 and 14 proteins associated with BMI at blood sampling and changes in BMI, respectively. The average heritability of these proteins was 35\%. Of the 66 BMI-protein associations, 43 and 12 showed genetic and environmental correlations, respectively, including 8 proteins showing both. Similarly, we observed 6 and 4 genetic and environmental correlations between changes in BMI and protein abundance, respectively. S100A8 gene expression was associated with BMI at blood sampling, and the PRG4 and CFI genes were associated with BMI changes. Proteins showed strong connections with many metabolites and PRSs, but we observed no multi-omics connections among gene expression and other omics layers. Conclusions: Associations between the proteome and BMI trajectories are characterized by shared genetic, environmental, and metabolic etiologies. We observed few gene-protein pairs associated with BMI or changes in BMI at the proteome and transcriptome levels.

}, doi = {10.1101/2023.06.28.23291995}, author = {Drouard, Gabin and Hagenbeek, Fiona A and Whipp, Alyce and Pool, Ren{\'e} and Hottenga, Jouke-Jan and Jansen, Rick and Hubers, Nikki and Afonin, Aleksei and Willemsen, Gonneke and de Geus, Eco J C and Ripatti, Samuli and Pirinen, Matti and Kanninen, Katja M and Boomsma, Dorret I and van Dongen, Jenny and Kaprio, Jaakko and BIOS Consortium and BBMRI-NL Metabolomics Consortium} } @inbook {372, title = {Chapter 32 - Twins and omics: the role of twin studies in multi-omics}, booktitle = {Twin Research for Everyone}, year = {2022}, pages = {547-584}, publisher = {Academic Press}, organization = {Academic Press}, abstract = {

Genomics, transcriptomics, proteomics, and metabolomics are the four main omics domains, referring to high-throughput studies of the genome (DNA), transcriptome (RNA), proteome (proteins), and metabolome (metabolites). Together, these omics domains describe how proteins are formed by the transcription and translation of genetic information and how cells, tissues, and organisms\’ function at the molecular level. Other omics layers reflect regulatory and modulatory processes or exposures to the environment. Twin designs offer powerful analytical tools to study variation in omics data and the influence of omics on phenotypes and phenotypic development. Here, we review and discuss the contribution of twin studies to omics and argue that twin research plays a valuable role in omics research.

}, keywords = {epigenome, Genome, Metabolome, Omics, Transcriptome, Twin design, twins}, isbn = {978-0-12-821514-2}, doi = {https://doi.org/10.1016/B978-0-12-821514-2.00029-5}, url = {https://www.sciencedirect.com/science/article/pii/B9780128215142000295}, author = {Fiona A. Hagenbeek and Jenny van Dongen and Ren{\`e} Pool and Dorret I. Boomsma}, editor = {Adam Tarnoki and David Tarnoki and Jennifer Harris and Nancy Segal} } @article {367, title = {Developmental co-occurrence of psychopathology dimensions in childhood}, journal = {JCPP Advances}, volume = {2}, year = {2022}, pages = {e12100}, abstract = {

Background: Comorbidity between psychopathologies may be attributed to genetic and environmental differences between people as well as causal processes within individuals, where one pathology increases risk for another. Disentangling between-person (co)variance from within-person processes of psychopathology dimensions across childhood may shed light on developmental causes of comorbid mental health problems. Here, we aim to determine whether and to what extent directional relationships between psychopathology dimensions within-person, and between individuals within families, play a role in comorbidity. Methods: We conducted random intercepts cross-lagged panel model (RI-CLPM) analyses to unravel the longitudinal co-occurrence of child psychopathology dimensions, jointly estimating between-person and within-person processes from childhood to early adolescence (age 7-12). We further developed an extension of the model to estimate sibling effects within-family (wf-RI-CLPM). Analyses were separately conducted in two large population-based cohorts, TEDS and NTR, including parent-rated measures of child problem behaviours based on the SDQ and CBCL scales respectively. Results: We found evidence for strong between-person effects underlying the positive intercorrelation between problem behaviours across time. Beyond these time-varying within-person processes accounted for an increasing amount of trait variance, within- and cross-trait, overtime in both cohorts. Lastly, by accommodating family level data, we found evidence for reciprocal directional influences within sib-pairs longitudinally. Conclusions: Our results indicate that within-person processes partly explain the co-occurrence of psychopathology dimensions across childhood, and within sib-pairs. Analyses provided substantive results on developmental processes underlying comorbidity in behavioural problems. Future studies should consider different developmental timeframes to shed more light on the processes contributing to developmental comorbidity.

}, keywords = {comorbidity, development, genetic and environmental effects, psychopathology, sibling effects}, doi = {10.1002/jcv2.12100}, author = {Allegrini, Andrea G and van Beijsterveldt, Toos and Boomsma, Dorret I and Rimfeld, Kaili and Pingault, Jean-Baptiste and Plomin, Robert and Bartels, Meike and Nivard, Michel G} } @article {376, title = {DNA methylation in peripheral tissues and left-handedness}, journal = {Nature Scientific Reports}, volume = {12}, year = {2022}, pages = {5606}, abstract = {

Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355-0.578]), but inconsistent across tissues (correlation range [- 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.

}, doi = {10.1038/s41598-022-08998-0}, author = {Odintsova, Veronika V and Suderman, Matthew and Hagenbeek, Fiona A and Caramaschi, Doretta and Hottenga, Jouke-Jan and Pool, Ren{\'e} and BIOS Consortium and Dolan, Conor V and Ligthart, Lannie and van Beijsterveldt, Catharina E M and Willemsen, Gonneke and de Geus, Eco J C and Beck, Jeffrey J and Ehli, Erik A and Cuellar-Partida, Gabriel and Evans, David M and Medland, Sarah E and Relton, Caroline L and Boomsma, Dorret I and van Dongen, Jenny} } @article {369, title = {Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people}, journal = {Proceedings of the National Academy of Sciences U. S. A.}, volume = {119}, year = {2022}, pages = {e2202764119}, abstract = {

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80\% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs1120800

}, keywords = {genome-wide association study, language, Meta-analysis, reading}, doi = {10.1073/pnas.2202764119}, author = {Eising, Else and Mirza-Schreiber, Nazanin and de Zeeuw, Eveline L and Wang, Carol A and Truong, Dongnhu T and Allegrini, Andrea G and Shapland, Chin Yang and Zhu, Gu and Wigg, Karen G and Gerritse, Margot L and Molz, Barbara and Alag{\"o}z, G{\"o}kberk and Gialluisi, Alessandro and Abbondanza, Filippo and Rimfeld, Kaili and van Donkelaar, Marjolein and Liao, Zhijie and Jansen, Philip R and Andlauer, Till F M and Bates, Timothy C and Bernard, Manon and Blokland, Kirsten and Bonte, Milene and B{\o}rglum, Anders D and Bourgeron, Thomas and Brandeis, Daniel and Ceroni, Fabiola and Cs{\'e}pe, Val{\'e}ria and Dale, Philip S and de Jong, Peter F and DeFries, John C and D{\'e}monet, Jean-Fran\c cois and Demontis, Ditte and Feng, Yu and Gordon, Scott D and Guger, Sharon L and Hayiou-Thomas, Marianna E and Hern{\'a}ndez-Cabrera, Juan A and Hottenga, Jouke-Jan and Hulme, Charles and Kere, Juha and Kerr, Elizabeth N and Koomar, Tanner and Landerl, Karin and Leonard, Gabriel T and Lovett, Maureen W and Lyytinen, Heikki and Martin, Nicholas G and Martinelli, Angela and Maurer, Urs and Michaelson, Jacob J and Moll, Kristina and Monaco, Anthony P and Morgan, Angela T and N{\"o}then, Markus M and Pausova, Zdenka and Pennell, Craig E and Pennington, Bruce F and Price, Kaitlyn M and Rajagopal, Veera M and Ramus, Franck and Richer, Louis and Simpson, Nuala H and Smith, Shelley D and Snowling, Margaret J and Stein, John and Strug, Lisa J and Talcott, Joel B and Tiemeier, Henning and van der Schroeff, Marc P and Verhoef, Ellen and Watkins, Kate E and Wilkinson, Margaret and Wright, Margaret J and Barr, Cathy L and Boomsma, Dorret I and Carreiras, Manuel and Franken, Marie-Christine J and Gruen, Jeffrey R and Luciano, Michelle and M{\"u}ller-Myhsok, Bertram and Newbury, Dianne F and Olson, Richard K and Paracchini, Silvia and Paus, Tom{\'a}\v s and Plomin, Robert and Reilly, Sheena and Schulte-K{\"o}rne, Gerd and Tomblin, J Bruce and van Bergen, Elsje and Whitehouse, Andrew J O and Willcutt, Erik G and St Pourcain, Beate and Francks, Clyde and Fisher, Simon E} } @article {380, title = {Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention}, journal = {Nature Genetics}, volume = {54}, year = {2022}, pages = {1332{\textendash}1344}, abstract = {

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

}, doi = {10.1038/s41588-022-01165-1}, author = {Wang, Zhe and Emmerich, Andrew and Pillon, Nicolas J and Moore, Tim and Hemerich, Daiane and Cornelis, Marilyn C and Mazzaferro, Eugenia and Broos, Siacia and Ahluwalia, Tarunveer S and Bartz, Traci M and Bentley, Amy R and Bielak, Lawrence F and Chong, Mike and Chu, Audrey Y and Berry, Diane and Dorajoo, Rajkumar and Dueker, Nicole D and Kasbohm, Elisa and Feenstra, Bjarke and Feitosa, Mary F and Gieger, Christian and Graff, Mariaelisa and Hall, Leanne M and Haller, Toomas and Hartwig, Fernando P and Hillis, David A and Huikari, Ville and Heard-Costa, Nancy and Holzapfel, Christina and Jackson, Anne U and Johansson, \AAsa and J{\o}rgensen, Anja Moltke and Kaakinen, Marika A and Karlsson, Robert and Kerr, Kathleen F and Kim, Boram and Koolhaas, Chantal M and Kutalik, Zoltan and Lagou, Vasiliki and Lind, Penelope A and Lorentzon, Mattias and Lyytik{\"a}inen, Leo-Pekka and Mangino, Massimo and Metzendorf, Christoph and Monroe, Kristine R and Pacolet, Alexander and P{\'e}russe, Louis and Pool, Ren{\'e} and Richmond, Rebecca C and Rivera, Natalia V and Robiou-du-Pont, Sebastien and Schraut, Katharina E and Schulz, Christina-Alexandra and Stringham, Heather M and Tanaka, Toshiko and Teumer, Alexander and Turman, Constance and van der Most, Peter J and Vanmunster, Mathias and van Rooij, Frank J A and van Vliet-Ostaptchouk, Jana V and Zhang, Xiaoshuai and Zhao, Jing-Hua and Zhao, Wei and Balkhiyarova, Zhanna and Balslev-Harder, Marie N and Baumeister, Sebastian E and Beilby, John and Blangero, John and Boomsma, Dorret I and Brage, Soren and Braund, Peter S and Brody, Jennifer A and Bruinenberg, Marcel and Ekelund, Ulf and Liu, Ching-Ti and Cole, John W and Collins, Francis S and Cupples, L Adrienne and Esko, T{\~o}nu and Enroth, Stefan and Faul, Jessica D and Fernandez-Rhodes, Lindsay and Fohner, Alison E and Franco, Oscar H and Galesloot, Tessel E and Gordon, Scott D and Grarup, Niels and Hartman, Catharina A and Heiss, Gerardo and Hui, Jennie and Illig, Thomas and Jago, Russell and James, Alan and Joshi, Peter K and Jung, Taeyeong and K{\"a}h{\"o}nen, Mika and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Kolcic, Ivana and Kraft, Peter P and Kuusisto, Johanna and Launer, Lenore J and Li, Aihua and Linneberg, Allan and Luan, Jian{\textquoteright}an and Vidal, Pedro Marques and Medland, Sarah E and Milaneschi, Yuri and Moscati, Arden and Musk, Bill and Nelson, Christopher P and Nolte, Ilja M and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Power, Christine and Raitakari, Olli T and Reedik, M{\"a}gi and Reiner, Alex P and Ridker, Paul M and Rudan, Igor and Ryan, Kathy and Sarzynski, Mark A and Scott, Laura J and Scott, Robert A and Sidney, Stephen and Siggeirsdottir, Kristin and Smith, Albert V and Smith, Jennifer A and Sonestedt, Emily and Str{\o}m, Marin and Tai, E Shyong and Teo, Koon K and Thorand, Barbara and T{\"o}njes, Anke and Tremblay, Angelo and Uitterlinden, Andr{\'e} G and Vangipurapu, Jagadish and van Schoor, Natasja and V{\"o}lker, Uwe and Willemsen, Gonneke and Williams, Kayleen and Wong, Quenna and Xu, Huichun and Young, Kristin L and Yuan, Jian Min and Zillikens, M Carola and Zonderman, Alan B and Ameur, Adam and Bandinelli, Stefania and Bis, Joshua C and Boehnke, Michael and Bouchard, Claude and Chasman, Daniel I and Smith, George Davey and de Geus, Eco J C and Deldicque, Louise and D{\"o}rr, Marcus and Evans, Michele K and Ferrucci, Luigi and Fornage, Myriam and Fox, Caroline and Garland, Jr, Theodore and Gudnason, Vilmundur and Gyllensten, Ulf and Hansen, Torben and Hayward, Caroline and Horta, Bernardo L and Hypponen, Elina and Jarvelin, Marjo-Riitta and Johnson, W Craig and Kardia, Sharon L R and Kiemeney, Lambertus A and Laakso, Markku and Langenberg, Claudia and Lehtim{\"a}ki, Terho and Marchand, Loic Le and Lifelines Cohort Study and Magnusson, Patrik K E and Martin, Nicholas G and Melbye, Mads and Metspalu, Andres and Meyre, David and North, Kari E and Ohlsson, Claes and Oldehinkel, Albertine J and Orho-Melander, Marju and Pare, Guillaume and Park, Taesung and Pedersen, Oluf and Penninx, Brenda W J H and Pers, Tune H and Polasek, Ozren and Prokopenko, Inga and Rotimi, Charles N and Samani, Nilesh J and Sim, Xueling and Snieder, Harold and S{\o}rensen, Thorkild I A and Spector, Tim D and Timpson, Nicholas J and van Dam, Rob M and van der Velde, Nathalie and van Duijn, Cornelia M and Vollenweider, Peter and V{\"o}lzke, Henry and Voortman, Trudy and Waeber, G{\'e}rard and Wareham, Nicholas J and Weir, David R and Wichmann, Heinz-Erich and Wilson, James F and Hevener, Andrea L and Krook, Anna and Zierath, Juleen R and Thomis, Martine A I and Loos, Ruth J F and Hoed, Marcel den} } @article {373, title = {Genome-wide association meta-analysis of childhood and adolescent internalizing symptoms}, journal = {Journal of the American Academy of Child \& Adolescent Psychiatry}, volume = {61}, year = {2022}, pages = {934{\textendash}945}, abstract = {

OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence.

METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument.

RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66\%, 95\% CI = 0.84-2.48

}, keywords = {anxiety, depression, genetic epidemiology, molecular genetics, repeated measures}, doi = {10.1016/j.jaac.2021.11.035}, author = {Jami, Eshim S and Hammerschlag, Anke R and Ip, Hill F and Allegrini, Andrea G and Benyamin, Beben and Border, Richard and Diemer, Elizabeth W and Jiang, Chang and Karhunen, Ville and Lu, Yi and Lu, Qing and Mallard, Travis T and Mishra, Pashupati P and Nolte, Ilja M and Palviainen, Teemu and Peterson, Roseann E and Sallis, Hannah M and Shabalin, Andrey A and Tate, Ashley E and Thiering, Elisabeth and Vilor-Tejedor, Nat{\`a}lia and Wang, Carol and Zhou, Ang and Adkins, Daniel E and Alemany, Silvia and Ask, Helga and Chen, Qi and Corley, Robin P and Ehli, Erik A and Evans, Luke M and Havdahl, Alexandra and Hagenbeek, Fiona A and Hakulinen, Christian and Henders, Anjali K and Hottenga, Jouke Jan and Korhonen, Tellervo and Mamun, Abdullah and Marrington, Shelby and Neumann, Alexander and Rimfeld, Kaili and Rivadeneira, Fernando and Silberg, Judy L and van Beijsterveldt, Catharina E and Vuoksimaa, Eero and Whipp, Alyce M and Tong, Xiaoran and Andreassen, Ole A and Boomsma, Dorret I and Brown, Sandra A and Burt, S Alexandra and Copeland, William and Dick, Danielle M and Harden, K Paige and Harris, Kathleen Mullan and Hartman, Catharina A and Heinrich, Joachim and Hewitt, John K and Hopfer, Christian and Hypponen, Elina and Jarvelin, Marjo-Riitta and Kaprio, Jaakko and Keltikangas-J{\"a}rvinen, Liisa and Klump, Kelly L and Krauter, Kenneth and Kuja-Halkola, Ralf and Larsson, Henrik and Lehtim{\"a}ki, Terho and Lichtenstein, Paul and Lundstr{\"o}m, Sebastian and Maes, Hermine H and Magnus, Per and Munaf{\`o}, Marcus R and Najman, Jake M and Nj{\o}lstad, P\aal R and Oldehinkel, Albertine J and Pennell, Craig E and Plomin, Robert and Reichborn-Kjennerud, Ted and Reynolds, Chandra and Rose, Richard J and Smolen, Andrew and Snieder, Harold and Stallings, Michael and Standl, Marie and Sunyer, Jordi and Tiemeier, Henning and Wadsworth, Sally J and Wall, Tamara L and Whitehouse, Andrew J O and Williams, Gail M and Ystr{\o}m, Eivind and Nivard, Michel G and Bartels, Meike and Middeldorp, Christel M} } @article {371, title = {Heritability of urinary amines, organic acids, and steroid hormones in children}, journal = {Metabolites}, volume = {12}, year = {2022}, pages = {474}, abstract = {

Variation in metabolite levels reflects individual differences in genetic and environmental factors. Here, we investigated the role of these factors in urinary metabolomics data in children. We examined the effects of sex and age on 86 metabolites, as measured on three metabolomics platforms that target amines, organic acids, and steroid hormones. Next, we estimated their heritability in a twin cohort of 1300 twins (age range: 5.7-12.9 years). We observed associations between age and 50 metabolites and between sex and 21 metabolites. The monozygotic (MZ) and dizygotic (DZ) correlations for the urinary metabolites indicated a role for non-additive genetic factors for 50 amines, 13 organic acids, and 6 steroids. The average broad-sense heritability for these amines, organic acids, and steroids was 0.49 (range: 0.25-0.64), 0.50 (range: 0.33-0.62), and 0.64 (range: 0.43-0.81), respectively. For 6 amines, 7 organic acids, and 4 steroids the twin correlations indicated a role for shared environmental factors and the average narrow-sense heritability was 0.50 (range: 0.37-0.68), 0.50 (range; 0.23-0.61), and 0.47 (range: 0.32-0.70) for these amines, organic acids, and steroids. We conclude that urinary metabolites in children have substantial heritability, with similar estimates for amines and organic acids, and higher estimates for steroid hormones.

}, keywords = {amines, children, classical twin design, heritability, metabolites, organic acids, steroid hormones, urine}, doi = {10.3390/metabo12060474}, author = {Hagenbeek, Fiona A and van Dongen, Jenny and Pool, Ren{\'e} and Harms, Amy C and Roetman, Peter J and Fanos, Vassilios and van Keulen, Britt J and Walker, Brian R and Karu, Naama and Hulshoff Pol, Hilleke E and Rotteveel, Joost and Finken, Martijn J J and Vermeiren, Robert R J M and Kluft, Cornelis and Bartels, Meike and Hankemeier, Thomas and Boomsma, Dorret I} } @article {378, title = {Overview of CAPICE-Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe-an EU Marie Sk{\l}odowska-Curie International Training Network}, journal = {European Child \& Adolescent Psychiatry}, volume = {31}, year = {2022}, pages = {829{\textendash}839}, abstract = {

The Roadmap for Mental Health and Wellbeing Research in Europe (ROAMER) identified child and adolescent mental illness as a priority area for research. CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) is a European Union (EU) funded training network aimed at investigating the causes of individual differences in common childhood and adolescent psychopathology, especially depression, anxiety, and attention deficit hyperactivity disorder. CAPICE brings together eight birth and childhood cohorts as well as other cohorts from the EArly Genetics and Life course Epidemiology (EAGLE) consortium, including twin cohorts, with unique longitudinal data on environmental exposures and mental health problems, and genetic data on participants. Here we describe the objectives, summarize the methodological approaches and initial results, and present the dissemination strategy of the CAPICE network. Besides identifying genetic and epigenetic variants associated with these phenotypes, analyses have been performed to shed light on the role of genetic factors and the interplay with the environment in influencing the persistence of symptoms across the lifespan. Data harmonization and building an advanced data catalogue are also part of the work plan. Findings will be disseminated to non-academic parties, in close collaboration with the Global Alliance of Mental Illness Advocacy Networks-Europe (GAMIAN-Europe).

}, keywords = {anxiety, Attention deficit hyperactivity disorder (ADHD), Childhood and adolescence psychopathology, depression, Psychiatric genetics}, doi = {10.1007/s00787-020-01713-2}, author = {Rajula, Hema Sekhar Reddy and Manchia, Mirko and Agarwal, Kratika and Akingbuwa, Wonuola A and Allegrini, Andrea G and Diemer, Elizabeth and Doering, Sabrina and Haan, Elis and Jami, Eshim S and Karhunen, Ville and Leone, Marica and Schellhas, Laura and Thompson, Ashley and van den Berg, St{\'e}phanie M and Bergen, Sarah E and Kuja-Halkola, Ralf and Hammerschlag, Anke R and J{\"a}rvelin, Marjo Riitta and Leval, Amy and Lichtenstein, Paul and Lundstr{\"o}m, Sebastian and Mauri, Matteo and Munaf{\`o}, Marcus R and Myers, David and Plomin, Robert and Rimfeld, Kaili and Tiemeier, Henning and Ystrom, Eivind and Fanos, Vassilios and Bartels, Meike and Middeldorp, Christel M} } @article {362, title = {1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans}, journal = {Translational Psychiatry}, volume = {11}, year = {2021}, pages = {182}, abstract = {

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48\% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

}, doi = {10.1038/s41398-021-01213-0}, author = {S{\o}nderby, Ida E and van der Meer, Dennis and Moreau, Clara and Kaufmann, Tobias and Walters, G Bragi and Ellegaard, Maria and Abdellaoui, Abdel and Ames, David and Amunts, Katrin and Andersson, Micael and Armstrong, Nicola J and Bernard, Manon and Blackburn, Nicholas B and Blangero, John and Boomsma, Dorret I and Brodaty, Henry and Brouwer, Rachel M and B{\"u}low, Robin and B{\o}en, Rune and Cahn, Wiepke and Calhoun, Vince D and Caspers, Svenja and Ching, Christopher R K and Cichon, Sven and Ciufolini, Simone and Crespo-Facorro, Benedicto and Curran, Joanne E and Dale, Anders M and Dalvie, Shareefa and Dazzan, Paola and de Geus, Eco J C and de Zubicaray, Greig I and de Zwarte, Sonja M C and Desrivi{\`e}res, Sylvane and Doherty, Joanne L and Donohoe, Gary and Draganski, Bogdan and Ehrlich, Stefan and Eising, Else and Espeseth, Thomas and Fejgin, Kim and Fisher, Simon E and Fladby, Tormod and Frei, Oleksandr and Frouin, Vincent and Fukunaga, Masaki and Gareau, Thomas and Ge, Tian and Glahn, David C and Grabe, Hans J and Groenewold, Nynke A and G{\'u}stafsson, {\'O}mar and Haavik, Jan and Haberg, Asta K and Hall, Jeremy and Hashimoto, Ryota and Hehir-Kwa, Jayne Y and Hibar, Derrek P and Hillegers, Manon H J and Hoffmann, Per and Holleran, Laurena and Holmes, Avram J and Homuth, Georg and Hottenga, Jouke-Jan and Hulshoff Pol, Hilleke E and Ikeda, Masashi and Jahanshad, Neda and Jockwitz, Christiane and Johansson, Stefan and J{\"o}nsson, Erik G and J{\o}rgensen, Niklas R and Kikuchi, Masataka and Knowles, Emma E M and Kumar, Kuldeep and Le Hellard, Stephanie and Leu, Costin and Linden, David E J and Liu, Jingyu and Lundervold, Arvid and Lundervold, Astri Johansen and Maillard, Anne M and Martin, Nicholas G and Martin-Brevet, Sandra and Mather, Karen A and Mathias, Samuel R and McMahon, Katie L and McRae, Allan F and Medland, Sarah E and Meyer-Lindenberg, Andreas and Moberget, Torgeir and Modenato, Claudia and S{\'a}nchez, Jennifer Monereo and Morris, Derek W and M{\"u}hleisen, Thomas W and Murray, Robin M and Nielsen, Jacob and Nordvik, Jan E and Nyberg, Lars and Loohuis, Loes M Olde and Ophoff, Roel A and Owen, Michael J and Paus, Tomas and Pausova, Zdenka and Peralta, Juan M and Pike, G Bruce and Prieto, Carlos and Quinlan, Erin B and Reinbold, C{\'e}line S and Marques, Tiago Reis and Rucker, James J H and Sachdev, Perminder S and Sando, Sigrid B and Schofield, Peter R and Schork, Andrew J and Schumann, Gunter and Shin, Jean and Shumskaya, Elena and Silva, Ana I and Sisodiya, Sanjay M and Steen, Vidar M and Stein, Dan J and Strike, Lachlan T and Suzuki, Ikuo K and Tamnes, Christian K and Teumer, Alexander and Thalamuthu, Anbupalam and Tordesillas-Guti{\'e}rrez, Diana and Uhlmann, Anne and Ulfarsson, Magnus O and van {\textquoteright}t Ent, Dennis and van den Bree, Marianne B M and Vanderhaeghen, Pierre and Vassos, Evangelos and Wen, Wei and Wittfeld, Katharina and Wright, Margaret J and Agartz, Ingrid and Djurovic, Srdjan and Westlye, Lars T and Stefansson, Hreinn and Stefansson, Kari and Jacquemont, S{\'e}bastien and Thompson, Paul M and Andreassen, Ole A and ENIGMA-CNV working group} } @inbook {358, title = {Combining twin-family designs with measured genetic variants to study the causes of epigenetic variation}, booktitle = {Twin and Family Studies of Epigenetics}, volume = {27}, number = {Translational Epigenetics}, year = {2021}, pages = {239{\textendash}259}, publisher = {Elsevier}, organization = {Elsevier}, chapter = {13}, abstract = {

Classical twin and family designs can be applied to examine the contribution of genetic and environmental influences to variation in epigenetic marks. Such models can be extended to allow for more in-depth questions, such as: How much of the variation in DNA methylation is explained by methylation Quantitative Trait Loci (QTLs)? Does the contribution of genetic or environmental influences differ between males and females or between younger and older individuals? Does methylation level at CpG site X have a causal effect on trait Y and vice versa, or is the association driven by genetic pleiotropy? In this chapter, we discuss twin designs that allow to address these questions. First, we describe models that incorporate genetic relationships based on genome-wide SNP data and the application of such models to DNA methylation data from adult twins and family members. Second, we discuss the value of an integration of Mendelian Randomization (MR) with the classical twin design.

}, doi = {https://doi.org/10.1016/B978-0-12-820951-6.00007-7}, author = {Minic\u a, Camelia C and Neale, Michael C and Boomsma, Dorret I and van Dongen, Jenny} } @inbook {351, title = {Discordant monozygotic twin studies of epigenetic mechanisms in mental health}, booktitle = {Twin and Family Studies of Epigenetics}, volume = {27}, number = {Translational Epigenetics}, year = {2021}, pages = {43{\textendash}66}, publisher = {Elsevier}, organization = {Elsevier}, chapter = {3}, abstract = {

The discordant monozygotic twin design is a strong method to assess causality. The design has been applied in a number of studies to investigate epigenetic mechanisms associated with mental health. These studies initially mainly focused on candidate genes and increasingly on genome-wide DNA methylation, gene expression, and X-chromosome inactivation, in various surrogate tissues such as blood and buccal cells, but also in brain tissue. In this chapter we review monozygotic twin studies of autism, aggressive behavior, ADHD, schizophrenia, bipolar disorder, and depression. We discuss the insights obtained by these studies and describe current limitations and challenges, including sample size, the use of surrogate tissues, causality, and confounders that apply to studies of cognitive and mental health such as medication use, lifestyle, and cellular heterogeneity of commonly investigated tissues.

}, doi = {https://doi.org/10.1016/B978-0-12-820951-6.00003-X}, author = {van Dongen, Jenny and Odintsova, Veronika V and Boomsma, Dorret I} } @article {349, title = {DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan}, journal = {Molecular Psychiatry}, volume = {26}, year = {2021}, pages = {2148{\textendash}2162}, abstract = {

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 $\times$ 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83\% of these sites showed the same direction of association with childhood aggression (r = 0.7

}, doi = {10.1038/s41380-020-00987-x}, author = {van Dongen, Jenny and Hagenbeek, Fiona A and Suderman, Matthew and Roetman, Peter J and Sugden, Karen and Chiocchetti, Andreas G and Ismail, Khadeeja and Mulder, Rosa H and Hafferty, Jonathan D and Adams, Mark J and Walker, Rosie M and Morris, Stewart W and Lahti, Jari and K{\"u}pers, Leanne K and Escaramis, Georgia and Alemany, Silvia and Jan Bonder, Marc and Meijer, Mandy and Ip, Hill F and Jansen, Rick and Baselmans, Bart M L and Parmar, Priyanka and Lowry, Estelle and Streit, Fabian and Sirignano, Lea and Send, Tabea S and Frank, Josef and Jylh{\"a}v{\"a}, Juulia and Wang, Yunzhang and Mishra, Pashupati Prasad and Colins, Olivier F and Corcoran, David L and Poulton, Richie and Mill, Jonathan and Hannon, Eilis and Arseneault, Louise and Korhonen, Tellervo and Vuoksimaa, Eero and Felix, Janine F and Bakermans-Kranenburg, Marian J and Campbell, Archie and Czamara, Darina and Binder, Elisabeth and Corpeleijn, Eva and Gonzalez, Juan R and Grazuleviciene, Regina and Gutzkow, Kristine B and Evandt, Jorunn and Vafeiadi, Marina and Klein, Marieke and van der Meer, Dennis and Ligthart, Lannie and BIOS Consortium and Kluft, Cornelis and Davies, Gareth E and Hakulinen, Christian and Keltikangas-J{\"a}rvinen, Liisa and Franke, Barbara and Freitag, Christine M and Konrad, Kerstin and Hervas, Amaia and Fern{\'a}ndez-Rivas, Aranzazu and Vetro, Agnes and Raitakari, Olli and Lehtim{\"a}ki, Terho and Vermeiren, Robert and Strandberg, Timo and R{\"a}ikk{\"o}nen, Katri and Snieder, Harold and Witt, Stephanie H and Deuschle, Michael and Pedersen, Nancy L and H{\"a}gg, Sara and Sunyer, Jordi and Franke, Lude and Kaprio, Jaakko and Ollikainen, Miina and Moffitt, Terrie E and Tiemeier, Henning and van IJzendoorn, Marinus H and Relton, Caroline and Vrijheid, Martine and Sebert, Sylvain and Jarvelin, Marjo-Riitta and Caspi, Avshalom and Evans, Kathryn L and McIntosh, Andrew M and Bartels, Meike and Boomsma, Dorret I} } @article {353, title = {Genetic association study of childhood aggression across raters, instruments, and age}, journal = {Translational Psychiatry}, volume = {11}, year = {2021}, pages = {413}, abstract = {

Childhood aggressive behavior (AGG) has a substantial heritability of around 50\%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31\% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44\%) and in retrospectively assessed childhood aggression (variance explained = 0.20\%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = \ -0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

}, doi = {10.1038/s41398-021-01480-x}, author = {Ip, Hill F and Van der Laan, Camiel M and Krapohl, Eva M L and Brikell, Isabell and S{\'a}nchez-Mora, Cristina and Nolte, Ilja M and St Pourcain, Beate and Bolhuis, Koen and Palviainen, Teemu and Zafarmand, Hadi and Colodro-Conde, Luc{\'\i}a and Gordon, Scott and Zayats, Tetyana and Aliev, Fazil and Jiang, Chang and Wang, Carol A and Saunders, Gretchen and Karhunen, Ville and Hammerschlag, Anke R and Adkins, Daniel E and Border, Richard and Peterson, Roseann E and Prinz, Joseph A and Thiering, Elisabeth and Sepp{\"a}l{\"a}, Ilkka and Vilor-Tejedor, Nat{\`a}lia and Ahluwalia, Tarunveer S and Day, Felix R and Hottenga, Jouke-Jan and Allegrini, Andrea G and Rimfeld, Kaili and Chen, Qi and Lu, Yi and Martin, Joanna and Soler Artigas, Mar{\'\i}a and Rovira, Paula and Bosch, Rosa and Espa{\~n}ol, Gemma and Ramos Quiroga, Josep Antoni and Neumann, Alexander and Ensink, Judith and Grasby, Katrina and Morosoli, Jos{\'e} J and Tong, Xiaoran and Marrington, Shelby and Middeldorp, Christel and Scott, James G and Vinkhuyzen, Anna and Shabalin, Andrey A and Corley, Robin and Evans, Luke M and Sugden, Karen and Alemany, Silvia and Sass, L{\ae}rke and Vinding, Rebecca and Ruth, Kate and Tyrrell, Jess and Davies, Gareth E and Ehli, Erik A and Hagenbeek, Fiona A and de Zeeuw, Eveline and van Beijsterveldt, Toos C E M and Larsson, Henrik and Snieder, Harold and Verhulst, Frank C and Amin, Najaf and Whipp, Alyce M and Korhonen, Tellervo and Vuoksimaa, Eero and Rose, Richard J and Uitterlinden, Andr{\'e} G and Heath, Andrew C and Madden, Pamela and Haavik, Jan and Harris, Jennifer R and Helgeland, {\O}yvind and Johansson, Stefan and Knudsen, Gun Peggy S and Njolstad, Pal Rasmus and Lu, Qing and Rodriguez, Alina and Henders, Anjali K and Mamun, Abdullah and Najman, Jackob M and Brown, Sandy and Hopfer, Christian and Krauter, Kenneth and Reynolds, Chandra and Smolen, Andrew and Stallings, Michael and Wadsworth, Sally and Wall, Tamara L and Silberg, Judy L and Miller, Allison and Keltikangas-J{\"a}rvinen, Liisa and Hakulinen, Christian and Pulkki-R\aaback, Laura and Havdahl, Alexandra and Magnus, Per and Raitakari, Olli T and Perry, John R B and Llop, Sabrina and Lopez-Espinosa, Maria-Jose and B{\o}nnelykke, Klaus and Bisgaard, Hans and Sunyer, Jordi and Lehtim{\"a}ki, Terho and Arseneault, Louise and Standl, Marie and Heinrich, Joachim and Boden, Joseph and Pearson, John and Horwood, L John and Kennedy, Martin and Poulton, Richie and Eaves, Lindon J and Maes, Hermine H and Hewitt, John and Copeland, William E and Costello, Elizabeth J and Williams, Gail M and Wray, Naomi and Jarvelin, Marjo-Riitta and McGue, Matt and Iacono, William and Caspi, Avshalom and Moffitt, Terrie E and Whitehouse, Andrew and Pennell, Craig E and Klump, Kelly L and Burt, S Alexandra and Dick, Danielle M and Reichborn-Kjennerud, Ted and Martin, Nicholas G and Medland, Sarah E and Vrijkotte, Tanja and Kaprio, Jaakko and Tiemeier, Henning and Davey Smith, George and Hartman, Catharina A and Oldehinkel, Albertine J and Casas, Miquel and Ribas{\'e}s, Marta and Lichtenstein, Paul and Lundstr{\"o}m, Sebastian and Plomin, Robert and Bartels, Meike and Nivard, Michel G and Boomsma, Dorret I} } @article {360, title = {Genetic insights into biological mechanisms governing human ovarian ageing}, journal = {Nature}, volume = {596}, year = {2021}, pages = {393{\textendash}397}, abstract = {

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1\% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

}, doi = {10.1038/s41586-021-03779-7}, author = {Ruth, Katherine S and Day, Felix R and Hussain, Jazib and Mart{\'\i}nez-Marchal, Ana and Aiken, Catherine E and Azad, Ajuna and Thompson, Deborah J and Knoblochova, Lucie and Abe, Hironori and Tarry-Adkins, Jane L and Gonzalez, Javier Martin and Fontanillas, Pierre and Claringbould, Annique and Bakker, Olivier B and Sulem, Patrick and Walters, Robin G and Terao, Chikashi and Turon, Sandra and Horikoshi, Momoko and Lin, Kuang and Onland-Moret, N Charlotte and Sankar, Aditya and Hertz, Emil Peter Thrane and Timshel, Pascal N and Shukla, Vallari and Borup, Rehannah and Olsen, Kristina W and Aguilera, Paula and Ferrer-Roda, M{\`o}nica and Huang, Yan and Stankovic, Stasa and Timmers, Paul R H J and Ahearn, Thomas U and Alizadeh, Behrooz Z and Naderi, Elnaz and Andrulis, Irene L and Arnold, Alice M and Aronson, Kristan J and Augustinsson, Annelie and Bandinelli, Stefania and Barbieri, Caterina M and Beaumont, Robin N and Becher, Heiko and Beckmann, Matthias W and Benonisdottir, Stefania and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Boomsma, Dorret I and Bowker, Nicholas and Brody, Jennifer A and Broer, Linda and Buring, Julie E and Campbell, Archie and Campbell, Harry and Castelao, Jose E and Catamo, Eulalia and Chanock, Stephen J and Chenevix-Trench, Georgia and Ciullo, Marina and Corre, Tanguy and Couch, Fergus J and Cox, Angela and Crisponi, Laura and Cross, Simon S and Cucca, Francesco and Czene, Kamila and Smith, George Davey and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Dunning, Alison M and Dwek, Miriam and Eriksson, Mikael and Esko, T{\~o}nu and Fasching, Peter A and Faul, Jessica D and Ferrucci, Luigi and Franceschini, Nora and Frayling, Timothy M and Gago-Dominguez, Manuela and Mezzavilla, Massimo and Garc{\'\i}a-Closas, Montserrat and Gieger, Christian and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Gu{\'e}nel, Pascal and Haiman, Christopher A and H\aakansson, Niclas and Hall, Per and Hayward, Caroline and He, Chunyan and He, Wei and Heiss, Gerardo and H{\o}ffding, Miya K and Hopper, John L and Hottenga, Jouke J and Hu, Frank and Hunter, David and Ikram, Mohammad A and Jackson, Rebecca D and Joaquim, Micaella D R and John, Esther M and Joshi, Peter K and Karasik, David and Kardia, Sharon L R and Kartsonaki, Christiana and Karlsson, Robert and Kitahara, Cari M and Kolcic, Ivana and Kooperberg, Charles and Kraft, Peter and Kurian, Allison W and Kutalik, Zoltan and La Bianca, Martina and LaChance, Genevieve and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lawlor, Deborah A and Le Marchand, Loic and Li, Jingmei and Lindblom, Annika and Lindstrom, Sara and Lindstrom, Tricia and Linet, Martha and Liu, Yongmei and Liu, Simin and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mangino, Massimo and Mannermaa, Arto and Marco, Brumat and Marten, Jonathan and Martin, Nicholas G and Mbarek, Hamdi and McKnight, Barbara and Medland, Sarah E and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mulas, Antonella and Mulligan, Anna M and Murray, Alison and Nalls, Mike A and Newman, Anne and Noordam, Raymond and Nutile, Teresa and Nyholt, Dale R and Olshan, Andrew F and Olsson, H\aakan and Painter, Jodie N and Patel, Alpa V and Pedersen, Nancy L and Perjakova, Natalia and Peters, Annette and Peters, Ulrike and Pharoah, Paul D P and Polasek, Ozren and Porcu, Eleonora and Psaty, Bruce M and Rahman, Iffat and Rennert, Gad and Rennert, Hedy S and Ridker, Paul M and Ring, Susan M and Robino, Antonietta and Rose, Lynda M and Rosendaal, Frits R and Rossouw, Jacques and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Saloustros, Emmanouil and Sandler, Dale P and Sanna, Serena and Sawyer, Elinor J and Sarnowski, Chlo{\'e} and Schlessinger, David and Schmidt, Marjanka K and Schoemaker, Minouk J and Schraut, Katharina E and Scott, Christopher and Shekari, Saleh and Shrikhande, Amruta and Smith, Albert V and Smith, Blair H and Smith, Jennifer A and Sorice, Rossella and Southey, Melissa C and Spector, Tim D and Spinelli, John J and Stampfer, Meir and St{\"o}ckl, Doris and van Meurs, Joyce B J and Strauch, Konstantin and Styrkarsdottir, Unnur and Swerdlow, Anthony J and Tanaka, Toshiko and Teras, Lauren R and Teumer, Alexander and {\TH}orsteinsdottir, Unnur and Timpson, Nicholas J and Toniolo, Daniela and Traglia, Michela and Troester, Melissa A and Truong, Th{\'e}r{\`e}se and Tyrrell, Jessica and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Vachon, Celine M and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and V{\"o}lzke, Henry and Wang, Qin and Wareham, Nicholas J and Weinberg, Clarice R and Weir, David R and Wilcox, Amber N and van Dijk, Ko Willems and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wolk, Alicja and Wood, Andrew R and Zhao, Wei and Zygmunt, Marek and Biobank-based Integrative Omics Study (BIOS) Consortium and eQTLGen Consortium and Biobank Japan Project and China Kadoorie Biobank Collaborative Group and kConFab Investigators and Lifelines Cohort Study and InterAct consortium and 23andMe Research Team and Chen, Zhengming and Li, Liming and Franke, Lude and Burgess, Stephen and Deelen, Patrick and Pers, Tune H and Gr{\o}ndahl, Marie Louise and Andersen, Claus Yding and Pujol, Anna and Lopez-Contreras, Andres J and Daniel, Jeremy A and Stefansson, Kari and Chang-Claude, Jenny and van der Schouw, Yvonne T and Lunetta, Kathryn L and Chasman, Daniel I and Easton, Douglas F and Visser, Jenny A and Ozanne, Susan E and Namekawa, Satoshi H and Solc, Petr and Murabito, Joanne M and Ong, Ken K and Hoffmann, Eva R and Murray, Anna and Roig, Ignasi and Perry, John R B} } @article {345, title = {Genetic meta-analysis of twin birth weight shows high genetic correlation with singleton birth weight}, journal = {Human Molecular Genetics}, volume = {30}, year = {2021}, pages = {1894{\textendash}1905}, abstract = {

Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson\&$\#$39;s r = 0.66, 95\% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95\% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.

}, doi = {10.1093/hmg/ddab121}, author = {Beck, Jeffrey J and Pool, Ren{\'e} and van de Weijer, Margot and Chen, Xu and Krapohl, Eva and Gordon, Scott D and Nygaard, Marianne and Debrabant, Birgit and Palviainen, Teemu and van der Zee, Matthijs D and Baselmans, Bart and Finnicum, Casey T and Yi, Lu and Lundstr{\"o}m, Sebastian and van Beijsterveldt, Toos and Christiansen, Lene and Heikkil{\"a}, Kauko and Kittelsrud, Julie and Loukola, Anu and Ollikainen, Miina and Christensen, Kaare and Martin, Nicholas G and Plomin, Robert and Nivard, Michel and Bartels, Meike and Dolan, Conor and Willemsen, Gonneke and de Geus, Eco and Almqvist, Catarina and Magnusson, Patrik K E and Mbarek, Hamdi and Ehli, Erik A and Boomsma, Dorret I and Hottenga, Jouke-Jan} } @article {346, title = {Genetically informed regression analysis: Application to aggression prediction by inattention and hyperactivity in children and adults}, journal = {Behavior Genetics}, volume = {51}, year = {2021}, pages = {250{\textendash}263}, abstract = {

We present a procedure to simultaneously fit a genetic covariance structure model and a regression model to multivariate data from mono- and dizygotic twin pairs to test for the prediction of a dependent trait by multiple correlated predictors. We applied the model to aggressive behavior as an outcome trait and investigated the prediction of aggression from inattention (InA) and hyperactivity (HA) in two age groups. Predictions were examined in twins with an average age of 10 years (11,345 pairs), and in adult twins with an average age of 30 years (7433 pairs). All phenotypes were assessed by the same, but age-appropriate, instruments in children and adults. Because of the different genetic architecture of aggression, InA and HA, a model was fitted to these data that specified additive and non-additive genetic factors (A and D) plus common and unique environmental (C and E) influences. Given appropriate identifying constraints, this ADCE model is identified in trivariate data. We obtained different results for the prediction of aggression in children, where HA was the more important predictor, and in adults, where InA was the more important predictor. In children, about 36\% of the total aggression variance was explained by the genetic and environmental components of HA and InA. Most of this was explained by the genetic components of HA and InA, i.e., 29.7\%, with 22.6\% due to the genetic component of HA. In adults, about 21\% of the aggression variance was explained. Most was this was again explained by the genetic components of InA and HA (16.2\%), with 8.6\% due to the genetic component of InA.

}, keywords = {Aggression, Genetic and environmental prediction, Hyperactivity, Inattention, Regression, Structural equation model}, doi = {10.1007/s10519-020-10025-9}, author = {Boomsma, Dorret I and van Beijsterveldt, Toos C E M and Odintsova, Veronika V and Neale, Michael C and Dolan, Conor V} } @article {364, title = {Higher aggression is related to poorer academic performance in compulsory education}, journal = {Journal of Child Psychology and Psychiatry}, volume = {62}, year = {2021}, pages = {327{\textendash}338}, abstract = {

BACKGROUND: To conduct a comprehensive assessment of the association between aggression and academic performance in compulsory education.

METHOD: We studied aggression and academic performance in over 27,000 individuals from four European twin cohorts participating in the ACTION consortium (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies). Individual level data on aggression at ages 7-16 were assessed by three instruments (Achenbach System of Empirically Based Assessment, Multidimensional Peer Nomination Inventory, Strengths and Difficulties Questionnaire) including parental, teacher and self-reports. Academic performance was measured with teacher-rated grade point averages (ages 12-14) or standardized test scores (ages 12-16). Random effect meta-analytical correlations with academic performance were estimated for parental ratings (in all four cohorts) and self-ratings (in three cohorts).

RESULTS: All between-family analyses indicated significant negative aggression-academic performance associations with correlations ranging from -.06 to -.33. Results were similar across different ages, instruments and raters and either with teacher-rated grade point averages or standardized test scores as measures of academic performance. Meta-analytical r\&$\#$39;s were -.20 and -.23 for parental and self-ratings, respectively. In within-family analyses of all twin pairs, the negative aggression-academic performance associations were statistically significant in 14 out of 17 analyses (r = -.17 for parental- and r = -.16 for self-ratings). Separate analyses in monozygotic (r = -.07 for parental and self-ratings), same-sex dizygotic (r\&$\#$39;s = -.16 and -.17 for parental and self-ratings) and opposite-sex dizygotic (r\&$\#$39;s = -.21 and -.19 for parental and self-ratings) twin pairs suggested partial confounding by genetic effects.

CONCLUSIONS: There is a robust negative association between aggression and academic performance in compulsory education. Part of these associations were explained by shared genetic effects, but some evidence of a negative association between aggression and academic performance remained even in within-family analyses of monozygotic twin pairs.

}, keywords = {Aggression, cognition, development, educational attainment, school performance}, doi = {10.1111/jcpp.13273}, author = {Vuoksimaa, Eero and Rose, Richard J and Pulkkinen, Lea and Palviainen, Teemu and Rimfeld, Kaili and Lundstr{\"o}m, Sebastian and Bartels, Meike and van Beijsterveldt, Catharina and Hendriks, Anne and de Zeeuw, Eveline L and Plomin, Robert and Lichtenstein, Paul and Boomsma, Dorret I and Kaprio, Jaakko} } @article {340, title = {Higher aggression is related to poorer academic performance in compulsory education}, journal = {Journal of Child Psychology and Psychiatry}, volume = {62}, year = {2021}, pages = {327{\textendash}338}, abstract = {

BACKGROUND: To conduct a comprehensive assessment of the association between aggression and academic performance in compulsory education.

METHOD: We studied aggression and academic performance in over 27,000 individuals from four European twin cohorts participating in the ACTION consortium (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies). Individual level data on aggression at ages 7-16 were assessed by three instruments (Achenbach System of Empirically Based Assessment, Multidimensional Peer Nomination Inventory, Strengths and Difficulties Questionnaire) including parental, teacher and self-reports. Academic performance was measured with teacher-rated grade point averages (ages 12-14) or standardized test scores (ages 12-16). Random effect meta-analytical correlations with academic performance were estimated for parental ratings (in all four cohorts) and self-ratings (in three cohorts).

RESULTS: All between-family analyses indicated significant negative aggression-academic performance associations with correlations ranging from -.06 to -.33. Results were similar across different ages, instruments and raters and either with teacher-rated grade point averages or standardized test scores as measures of academic performance. Meta-analytical r\&$\#$39;s were -.20 and -.23 for parental and self-ratings, respectively. In within-family analyses of all twin pairs, the negative aggression-academic performance associations were statistically significant in 14 out of 17 analyses (r = -.17 for parental- and r = -.16 for self-ratings). Separate analyses in monozygotic (r = -.07 for parental and self-ratings), same-sex dizygotic (r\&$\#$39;s = -.16 and -.17 for parental and self-ratings) and opposite-sex dizygotic (r\&$\#$39;s = -.21 and -.19 for parental and self-ratings) twin pairs suggested partial confounding by genetic effects.

CONCLUSIONS: There is a robust negative association between aggression and academic performance in compulsory education. Part of these associations were explained by shared genetic effects, but some evidence of a negative association between aggression and academic performance remained even in within-family analyses of monozygotic twin pairs.

}, keywords = {Aggression, cognition, development, educational attainment, school performance}, doi = {10.1111/jcpp.13273}, author = {Vuoksimaa, Eero and Rose, Richard J and Pulkkinen, Lea and Palviainen, Teemu and Rimfeld, Kaili and Lundstr{\"o}m, Sebastian and Bartels, Meike and van Beijsterveldt, Catharina and Hendriks, Anne and de Zeeuw, Eveline L and Plomin, Robert and Lichtenstein, Paul and Boomsma, Dorret I and Kaprio, Jaakko} } @article {350, title = {Identical twins carry a persistent epigenetic signature of early genome programming}, journal = {Nature Communications}, volume = {12}, year = {2021}, pages = {5618}, abstract = {

Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin.

}, doi = {10.1038/s41467-021-25583-7}, author = {van Dongen, Jenny and Gordon, Scott D and McRae, Allan F and Odintsova, Veronika V and Mbarek, Hamdi and Breeze, Charles E and Sugden, Karen and Lundgren, Sara and Castillo-Fernandez, Juan E and Hannon, Eilis and Moffitt, Terrie E and Hagenbeek, Fiona A and van Beijsterveldt, Catharina E M and Jan Hottenga, Jouke and Tsai, Pei-Chien and BIOS Consortium and Genetics of DNA Methylation Consortium and Min, Josine L and Hemani, Gibran and Ehli, Erik A and Paul, Franziska and Stern, Claudio D and Heijmans, Bastiaan T and Slagboom, P Eline and Daxinger, Lucia and van der Maarel, Silv{\`e}re M and de Geus, Eco J C and Willemsen, Gonneke and Montgomery, Grant W and Reversade, Bruno and Ollikainen, Miina and Kaprio, Jaakko and Spector, Tim D and Bell, Jordana T and Mill, Jonathan and Caspi, Avshalom and Martin, Nicholas G and Boomsma, Dorret I} } @article {357, title = {Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour}, journal = {Nature Human Behaviour}, volume = {5}, year = {2021}, pages = {1717{\textendash}1730}, abstract = {

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N\ =\ 387,338; age at first birth, N\ =\ 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5\–6\% polygenic score prediction. Heritability of age at first birth shifted from 9\% [CI\ =\ 4\–14\%] for women born in 1940 to 22\% [CI\ =\ 19\–25\%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90\%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

}, doi = {10.1038/s41562-021-01135-3}, author = {Mills, Melinda C and Tropf, Felix C and Brazel, David M and van Zuydam, Natalie and Vaez, Ahmad and eQTLGen Consortium and BIOS Consortium and Human Reproductive Behaviour Consortium and Pers, Tune H and Snieder, Harold and Perry, John R B and Ong, Ken K and den Hoed, Marcel and Barban, Nicola and Day, Felix R} } @article {348, title = {Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction}, journal = {Nature Genetics}, volume = {53}, year = {2021}, pages = {35{\textendash}44}, abstract = {

Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57\% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.

}, doi = {10.1038/s41588-020-00754-2}, author = {Demange, Perline A and Malanchini, Margherita and Mallard, Travis T and Biroli, Pietro and Cox, Simon R and Grotzinger, Andrew D and Tucker-Drob, Elliot M and Abdellaoui, Abdel and Arseneault, Louise and van Bergen, Elsje and Boomsma, Dorret I and Caspi, Avshalom and Corcoran, David L and Domingue, Benjamin W and Harris, Kathleen Mullan and Ip, Hill F and Mitchell, Colter and Moffitt, Terrie E and Poulton, Richie and Prinz, Joseph A and Sugden, Karen and Wertz, Jasmin and Williams, Benjamin S and de Zeeuw, Eveline L and Belsky, Daniel W and Harden, K Paige and Nivard, Michel G} } @article {365, title = {Ketone body 3-hydroxybutyrate as a biomarker of aggression}, journal = {Nature Scientific Reports}, volume = {11}, year = {2021}, pages = {5813}, abstract = {

Human aggression is a complex behaviour, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983-1987, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the response variable and aggression ratings as predictor variables, and included several potential confounders. All metabolites showed low correlations with aggression, with only one-3-hydroxybutyrate, a ketone body produced during fasting-showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated (age 14) aggression were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher aggression (self-rated) was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.

}, doi = {10.1038/s41598-021-84635-6}, author = {Whipp, A M and Vuoksimaa, E and Korhonen, T and Pool, R and But, A and Ligthart, L and Hagenbeek, F A and Bartels, M and Bogl, L H and Pulkkinen, L and Rose, R J and Boomsma, D I and Kaprio, J} } @article {354, title = {Large-scale association analyses identify host factors influencing human gut microbiome composition}, journal = {Nature Genetics}, volume = {53}, year = {2021}, pages = {156{\textendash}165}, abstract = {

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95\% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P \< 5 $\times$ 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 $\times$ 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 $\times$ 10-10 \< P \< 5 $\times$ 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

}, doi = {10.1038/s41588-020-00763-1}, author = {Kurilshikov, Alexander and Medina-Gomez, Carolina and Bacigalupe, Rodrigo and Radjabzadeh, Djawad and Wang, Jun and Demirkan, Ayse and Le Roy, Caroline I and Raygoza Garay, Juan Antonio and Finnicum, Casey T and Liu, Xingrong and Zhernakova, Daria V and Bonder, Marc Jan and Hansen, Tue H and Frost, Fabian and R{\"u}hlemann, Malte C and Turpin, Williams and Moon, Jee-Young and Kim, Han-Na and L{\"u}ll, Kreete and Barkan, Elad and Shah, Shiraz A and Fornage, Myriam and Szopinska-Tokov, Joanna and Wallen, Zachary D and Borisevich, Dmitrii and Agreus, Lars and Andreasson, Anna and Bang, Corinna and Bedrani, Larbi and Bell, Jordana T and Bisgaard, Hans and Boehnke, Michael and Boomsma, Dorret I and Burk, Robert D and Claringbould, Annique and Croitoru, Kenneth and Davies, Gareth E and van Duijn, Cornelia M and Duijts, Liesbeth and Falony, Gwen and Fu, Jingyuan and van der Graaf, Adriaan and Hansen, Torben and Homuth, Georg and Hughes, David A and Ijzerman, Richard G and Jackson, Matthew A and Jaddoe, Vincent W V and Joossens, Marie and J{\o}rgensen, Torben and Keszthelyi, Daniel and Knight, Rob and Laakso, Markku and Laudes, Matthias and Launer, Lenore J and Lieb, Wolfgang and Lusis, Aldons J and Masclee, Ad A M and Moll, Henriette A and Mujagic, Zlatan and Qibin, Qi and Rothschild, Daphna and Shin, Hocheol and S{\o}rensen, S{\o}ren J and Steves, Claire J and Thorsen, Jonathan and Timpson, Nicholas J and Tito, Raul Y and Vieira-Silva, Sara and V{\"o}lker, Uwe and V{\"o}lzke, Henry and V{\~o}sa, Urmo and Wade, Kaitlin H and Walter, Susanna and Watanabe, Kyoko and Weiss, Stefan and Weiss, Frank U and Weissbrod, Omer and Westra, Harm-Jan and Willemsen, Gonneke and Payami, Haydeh and Jonkers, Daisy M A E and Arias Vasquez, Alejandro and de Geus, Eco J C and Meyer, Katie A and Stokholm, Jakob and Segal, Eran and Org, Elin and Wijmenga, Cisca and Kim, Hyung-Lae and Kaplan, Robert C and Spector, Tim D and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Franke, Andre and Lerch, Markus M and Franke, Lude and Sanna, Serena and D{\textquoteright}Amato, Mauro and Pedersen, Oluf and Paterson, Andrew D and Kraaij, Robert and Raes, Jeroen and Zhernakova, Alexandra} } @article {361, title = {Large-scale collaboration in ENIGMA-EEG: A perspective on the meta-analytic approach to link neurological and psychiatric liability genes to electrophysiological brain activity}, journal = {Brain and Behavior}, volume = {11}, year = {2021}, pages = {e02188}, abstract = {

BACKGROUND AND PURPOSE: The ENIGMA-EEG working group was established to enable large-scale international collaborations among cohorts that investigate the genetics of brain function measured with electroencephalography (EEG). In this perspective, we will discuss why analyzing the genetics of functional brain activity may be crucial for understanding how neurological and psychiatric liability genes affect the brain.

METHODS: We summarize how we have performed our currently largest genome-wide association study of oscillatory brain activity in EEG recordings by meta-analyzing the results across five participating cohorts, resulting in the first genome-wide significant hits for oscillatory brain function located in/near genes that were previously associated with psychiatric disorders. We describe how we have tackled methodological issues surrounding genetic meta-analysis of EEG features. We discuss the importance of harmonizing EEG signal processing, cleaning, and feature extraction. Finally, we explain our selection of EEG features currently being investigated, including the temporal dynamics of oscillations and the connectivity network based on synchronization of oscillations.

RESULTS: We present data that show how to perform systematic quality control and evaluate how choices in reference electrode and montage affect individual differences in EEG parameters.

CONCLUSION: The long list of potential challenges to our large-scale meta-analytic approach requires extensive effort and organization between participating cohorts; however, our perspective shows that these challenges are surmountable. Our perspective argues that elucidating the genetic of EEG oscillatory activity is a worthwhile effort in order to elucidate the pathway from gene to disease liability.

}, keywords = {brain disorders, electroencephalography, ENIGMA, harmonization, imaging genetics, open science}, doi = {10.1002/brb3.2188}, author = {Smit, Dirk J A and Andreassen, Ole A and Boomsma, Dorret I and Burwell, Scott J and Chorlian, David B and de Geus, Eco J C and Elvs\aashagen, Torbj{\o}rn and Gordon, Reyna L and Harper, Jeremy and Hegerl, Ulrich and Hensch, Tilman and Iacono, William G and Jawinski, Philippe and J{\"o}nsson, Erik G and Luykx, Jurjen J and Magne, Cyrille L and Malone, Stephen M and Medland, Sarah E and Meyers, Jacquelyn L and Moberget, Torgeir and Porjesz, Bernice and Sander, Christian and Sisodiya, Sanjay M and Thompson, Paul M and van Beijsterveldt, Catharina E M and van Dellen, Edwin and Via, Marc and Wright, Margaret J} } @article {363, title = {Parental age in relation to offspring{\textquoteright}s neurodevelopment}, journal = {Journal of Clinical Child \& Adolescent Psychology}, volume = {50}, year = {2021}, pages = {632{\textendash}644}, abstract = {

Objective: Advanced parenthood increases the risk of severe neurodevelopmental disorders like autism, Down syndrome and schizophrenia. Does advanced parenthood also negatively impact offspring\&$\#$39;s general neurodevelopment?Method: We analyzed child-, father-, mother- and teacher-rated attention-problems (N = 38,024), and standardized measures of intelligence (N = 10,273) and educational achievement (N = 17,522) of children from four Dutch population-based cohorts. The mean age over cohorts varied from 9.73-13.03. Most participants were of Dutch origin, ranging from 58.7\%-96.7\% over cohorts. We analyzed 50\% of the data to generate hypotheses and the other 50\% to evaluate support for these hypotheses. We aggregated the results over cohorts with Bayesian research synthesis.Results: We mostly found negative linear relations between parental age and attention-problems, meaning that offspring of younger parents tended to have more attention problems. Maternal age was positively and linearly related to offspring\&$\#$39;s IQ and educational achievement. Paternal age showed an attenuating positive relation with educational achievement and an inverted U-shape relation with IQ, with offspring of younger and older fathers at a disadvantage. Only the associations with maternal age remained after including SES. The inclusion of child gender in the model did not affect the relation between parental age and the study outcomes.Conclusions: Effects were small but significant, with better outcomes for children born to older parents. Older parents tended to be of higher SES. Indeed, the positive relation between parental age and offspring neurodevelopmental outcomes was partly confounded by SES.

}, doi = {10.1080/15374416.2020.1756298}, author = {Veldkamp, S A M and Zondervan-Zwijnenburg, M A J and van Bergen, Elsje and Barzeva, S A and Tamayo-Martinez, N and Becht, A I and van Beijsterveldt, C E M and Meeus, W and Branje, S and Hillegers, M H J and Oldehinkel, A J and Hoijtink, H J A and Boomsma, D I and Hartman, C} } @article {359, title = {Predicting complex traits and exposures from polygenic scores and blood and buccal DNA methylation profiles}, journal = {Frontiers in Psychiatry}, volume = {12}, year = {2021}, pages = {688464}, abstract = {

We examined the performance of methylation scores (MS) and polygenic scores (PGS) for birth weight, BMI, prenatal maternal smoking exposure, and smoking status to assess the extent to which MS could predict these traits and exposures over and above the PGS in a multi-omics prediction model. MS may be seen as the epigenetic equivalent of PGS, but because of their dynamic nature and sensitivity of non-genetic exposures may add to complex trait prediction independently of PGS. MS and PGS were calculated based on genotype data and DNA-methylation data in blood samples from adults (Illumina 450 K; N = 2,431; mean age 35.6) and in buccal samples from children (Illumina EPIC; N = 1,128; mean age 9.6) from the Netherlands Twin Register. Weights to construct the scores were obtained from results of large epigenome-wide association studies (EWASs) based on whole blood or cord blood methylation data and genome-wide association studies (GWASs). In adults, MSs in blood predicted independently from PGSs, and outperformed PGSs for BMI, prenatal maternal smoking, and smoking status, but not for birth weight. The largest amount of variance explained by the multi-omics prediction model was for current vs. never smoking (54.6\%) of which 54.4\% was captured by the MS. The two predictors captured 16\% of former vs. never smoking initiation variance (MS:15.5\%, PGS: 0.5\%), 17.7\% of prenatal maternal smoking variance (MS:16.9\%, PGS: 0.8\%), 11.9\% of BMI variance (MS: 6.4\%, PGS 5.5\%), and 1.9\% of birth weight variance (MS: 0.4\%, PGS: 1.5\%). In children, MSs in buccal samples did not show independent predictive value. The largest amount of variance explained by the two predictors was for prenatal maternal smoking (2.6\%), where the MSs contributed 1.5\%. These results demonstrate that blood DNA MS in adults explain substantial variance in current smoking, large variance in former smoking, prenatal smoking, and BMI, but not in birth weight. Buccal cell DNA methylation scores have lower predictive value, which could be due to different tissues in the EWAS discovery studies and target sample, as well as to different ages. This study illustrates the value of combining polygenic scores with information from methylation data for complex traits and exposure prediction.

}, keywords = {birth weight, BMI, DNA methylation, maternal smoking, methylation scores, multi-omics prediction, polygenic scores, smoking}, doi = {10.3389/fpsyt.2021.688464}, author = {Odintsova, Veronika V and Rebattu, Valerie and Hagenbeek, Fiona A and Pool, Ren{\'e} and Beck, Jeffrey J and Ehli, Erik A and van Beijsterveldt, Catharina E M and Ligthart, Lannie and Willemsen, Gonneke and de Geus, Eco J C and Hottenga, Jouke-Jan and Boomsma, Dorret I and van Dongen, Jenny} } @article {355, title = {Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability}, journal = {Nature Communications}, volume = {12}, year = {2021}, pages = {24}, abstract = {

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

}, doi = {10.1038/s41467-020-19366-9}, author = {Lagou, Vasiliki and M{\"a}gi, Reedik and Hottenga, Jouke- Jan and Grallert, Harald and Perry, John R B and Bouatia-Naji, Nabila and Marullo, Letizia and Rybin, Denis and Jansen, Rick and Min, Josine L and Dimas, Antigone S and Ulrich, Anna and Zudina, Liudmila and G\aadin, Jesper R and Jiang, Longda and Faggian, Alessia and Bonnefond, Am{\'e}lie and Fadista, Joao and Stathopoulou, Maria G and Isaacs, Aaron and Willems, Sara M and Navarro, Pau and Tanaka, Toshiko and Jackson, Anne U and Montasser, May E and O{\textquoteright}Connell, Jeff R and Bielak, Lawrence F and Webster, Rebecca J and Saxena, Richa and Stafford, Jeanette M and Pourcain, Beate St and Timpson, Nicholas J and Salo, Perttu and Shin, So-Youn and Amin, Najaf and Smith, Albert V and Li, Guo and Verweij, Niek and Goel, Anuj and Ford, Ian and Johnson, Paul C D and Johnson, Toby and Kapur, Karen and Thorleifsson, Gudmar and Strawbridge, Rona J and Rasmussen-Torvik, Laura J and Esko, T{\~o}nu and Mihailov, Evelin and Fall, Tove and Fraser, Ross M and Mahajan, Anubha and Kanoni, Stavroula and Giedraitis, Vilmantas and Kleber, Marcus E and Silbernagel, G{\"u}nther and Meyer, Julia and M{\"u}ller-Nurasyid, Martina and Ganna, Andrea and Sarin, Antti-Pekka and Yengo, Loic and Shungin, Dmitry and Luan, Jian{\textquoteright}an and Horikoshi, Momoko and An, Ping and Sanna, Serena and Boettcher, Yvonne and Rayner, N William and Nolte, Ilja M and Zemunik, Tatijana and van Iperen, Erik and Kovacs, Peter and Hastie, Nicholas D and Wild, Sarah H and McLachlan, Stela and Campbell, Susan and Polasek, Ozren and Carlson, Olga and Egan, Josephine and Kiess, Wieland and Willemsen, Gonneke and Kuusisto, Johanna and Laakso, Markku and Dimitriou, Maria and Hicks, Andrew A and Rauramaa, Rainer and Bandinelli, Stefania and Thorand, Barbara and Liu, Yongmei and Miljkovic, Iva and Lind, Lars and Doney, Alex and Perola, Markus and Hingorani, Aroon and Kivimaki, Mika and Kumari, Meena and Bennett, Amanda J and Groves, Christopher J and Herder, Christian and Koistinen, Heikki A and Kinnunen, Leena and Faire, Ulf de and Bakker, Stephan J L and Uusitupa, Matti and Palmer, Colin N A and Jukema, J Wouter and Sattar, Naveed and Pouta, Anneli and Snieder, Harold and Boerwinkle, Eric and Pankow, James S and Magnusson, Patrik K and Krus, Ulrika and Scapoli, Chiara and de Geus, Eco J C N and Bl{\"u}her, Matthias and Wolffenbuttel, Bruce H R and Province, Michael A and Abecasis, Goncalo R and Meigs, James B and Hovingh, G Kees and Lindstr{\"o}m, Jaana and Wilson, James F and Wright, Alan F and Dedoussis, George V and Bornstein, Stefan R and Schwarz, Peter E H and T{\"o}njes, Anke and Winkelmann, Bernhard R and Boehm, Bernhard O and M{\"a}rz, Winfried and Metspalu, Andres and Price, Jackie F and Deloukas, Panos and K{\"o}rner, Antje and Lakka, Timo A and Keinanen-Kiukaanniemi, Sirkka M and Saaristo, Timo E and Bergman, Richard N and Tuomilehto, Jaakko and Wareham, Nicholas J and Langenberg, Claudia and M{\"a}nnist{\"o}, Satu and Franks, Paul W and Hayward, Caroline and Vitart, Veronique and Kaprio, Jaakko and Visvikis-Siest, Sophie and Balkau, Beverley and Altshuler, David and Rudan, Igor and Stumvoll, Michael and Campbell, Harry and van Duijn, Cornelia M and Gieger, Christian and Illig, Thomas and Ferrucci, Luigi and Pedersen, Nancy L and Pramstaller, Peter P and Boehnke, Michael and Frayling, Timothy M and Shuldiner, Alan R and Peyser, Patricia A and Kardia, Sharon L R and Palmer, Lyle J and Penninx, Brenda W and Meneton, Pierre and Harris, Tamara B and Navis, Gerjan and Harst, Pim van der and Smith, George Davey and Forouhi, Nita G and Loos, Ruth J F and Salomaa, Veikko and Soranzo, Nicole and Boomsma, Dorret I and Groop, Leif and Tuomi, Tiinamaija and Hofman, Albert and Munroe, Patricia B and Gudnason, Vilmundur and Siscovick, David S and Watkins, Hugh and Lecoeur, Cecile and Vollenweider, Peter and Franco-Cereceda, Anders and Eriksson, Per and Jarvelin, Marjo-Riitta and Stefansson, Kari and Hamsten, Anders and Nicholson, George and Karpe, Fredrik and Dermitzakis, Emmanouil T and Lindgren, Cecilia M and McCarthy, Mark I and Froguel, Philippe and Kaakinen, Marika A and Lyssenko, Valeriya and Watanabe, Richard M and Ingelsson, Erik and Florez, Jose C and Dupuis, Jos{\'e}e and Barroso, In{\^e}s and Morris, Andrew P and Prokopenko, Inga and Meta-Analyses of Glucose and Insulin-related Traits Consortium (MAGIC)} } @article {366, title = {Teacher-rated aggression and co-occurring behaviors and emotional problems among schoolchildren in four population-based European cohorts}, journal = {PLoS One}, volume = {16}, year = {2021}, pages = {e0238667}, abstract = {

Aggressive behavior in school is an ongoing concern. The current focus is on specific manifestations such as bullying, but the behavior is broad and heterogenous. Children spend a substantial amount of time in school, but their behaviors in the school setting tend to be less well characterized than at home. Because aggression may index multiple behavioral problems, we used three validated instruments to assess means, correlations and gender differences of teacher-rated aggressive behavior with co-occurring externalizing/internalizing problems and social behavior in 39,936 schoolchildren aged 7-14 from 4 population-based cohorts from Finland, the Netherlands, and the UK. Correlations of aggressive behavior were high with all other externalizing problems (r: 0.47-0.80) and lower with internalizing problems (r: 0.02-0.39). A negative association was observed with prosocial behavior (r: -0.33 to -0.54). Mean levels of aggressive behavior differed significantly by gender. Despite the higher mean levels of aggressive behavior in boys, the correlations were notably similar for boys and girls (e.g., aggressive-hyperactivity correlations: 0.51-0.75 boys, 0.47-0.70 girls) and did not vary greatly with respect to age, instrument or cohort. Thus, teacher-rated aggressive behavior rarely occurs in isolation; boys and girls with problems of aggressive behavior likely require help with other behavioral and emotional problems. Important to note, higher aggressive behavior is not only associated with higher amounts of other externalizing and internalizing problems but also with lower levels of prosocial behavior.

}, doi = {10.1371/journal.pone.0238667}, author = {Whipp, Alyce M and Vuoksimaa, Eero and Bolhuis, Koen and de Zeeuw, Eveline L and Korhonen, Tellervo and Mauri, Matteo and Pulkkinen, Lea and Rimfeld, Kaili and Rose, Richard J and van Beijsterveldt, Catharina Toos E M and Bartels, Meike and Plomin, Robert and Tiemeier, Henning and Kaprio, Jaakko and Boomsma, Dorret I} } @article {347, title = {The trans-ancestral genomic architecture of glycemic traits}, journal = {Nature Genetics}, volume = {53}, year = {2021}, pages = {840{\textendash}860}, abstract = {

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30\% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P \< 5 $\times$ 10-8), 80\% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99\% credible sets by a median of 37.5\%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

}, doi = {10.1038/s41588-021-00852-9}, author = {Chen, Ji and Spracklen, Cassandra N and Marenne, Ga{\"e}lle and Varshney, Arushi and Corbin, Laura J and Luan, Jian{\textquoteright}an and Willems, Sara M and Wu, Ying and Zhang, Xiaoshuai and Horikoshi, Momoko and Boutin, Thibaud S and M{\"a}gi, Reedik and Waage, Johannes and Li-Gao, Ruifang and Chan, Kei Hang Katie and Yao, Jie and Anasanti, Mila D and Chu, Audrey Y and Claringbould, Annique and Heikkinen, Jani and Hong, Jaeyoung and Hottenga, Jouke-Jan and Huo, Shaofeng and Kaakinen, Marika A and Louie, Tin and M{\"a}rz, Winfried and Moreno-Macias, Hortensia and Ndungu, Anne and Nelson, Sarah C and Nolte, Ilja M and North, Kari E and Raulerson, Chelsea K and Ray, Debashree and Rohde, Rebecca and Rybin, Denis and Schurmann, Claudia and Sim, Xueling and Southam, Lorraine and Stewart, Isobel D and Wang, Carol A and Wang, Yujie and Wu, Peitao and Zhang, Weihua and Ahluwalia, Tarunveer S and Appel, Emil V R and Bielak, Lawrence F and Brody, Jennifer A and Burtt, No{\"e}l P and Cabrera, Claudia P and Cade, Brian E and Chai, Jin Fang and Chai, Xiaoran and Chang, Li-Ching and Chen, Chien-Hsiun and Chen, Brian H and Chitrala, Kumaraswamy Naidu and Chiu, Yen-Feng and de Haan, Hugoline G and Delgado, Graciela E and Demirkan, Ayse and Duan, Qing and Engmann, Jorgen and Fatumo, Segun A and Gay{\'a}n, Javier and Giulianini, Franco and Gong, Jung Ho and Gustafsson, Stefan and Hai, Yang and Hartwig, Fernando P and He, Jing and Heianza, Yoriko and Huang, Tao and Huerta-Chagoya, Alicia and Hwang, Mi Yeong and Jensen, Richard A and Kawaguchi, Takahisa and Kentistou, Katherine A and Kim, Young Jin and Kleber, Marcus E and Kooner, Ishminder K and Lai, Shuiqing and Lange, Leslie A and Langefeld, Carl D and Lauzon, Marie and Li, Man and Ligthart, Symen and Liu, Jun and Loh, Marie and Long, Jirong and Lyssenko, Valeriya and Mangino, Massimo and Marzi, Carola and Montasser, May E and Nag, Abhishek and Nakatochi, Masahiro and Noce, Damia and Noordam, Raymond and Pistis, Giorgio and Preuss, Michael and Raffield, Laura and Rasmussen-Torvik, Laura J and Rich, Stephen S and Robertson, Neil R and Rueedi, Rico and Ryan, Kathleen and Sanna, Serena and Saxena, Richa and Schraut, Katharina E and Sennblad, Bengt and Setoh, Kazuya and Smith, Albert V and Spars{\o}, Thomas and Strawbridge, Rona J and Takeuchi, Fumihiko and Tan, Jingyi and Trompet, Stella and van den Akker, Erik and van der Most, Peter J and Verweij, Niek and Vogel, Mandy and Wang, Heming and Wang, Chaolong and Wang, Nan and Warren, Helen R and Wen, Wanqing and Wilsgaard, Tom and Wong, Andrew and Wood, Andrew R and Xie, Tian and Zafarmand, Mohammad Hadi and Zhao, Jing-Hua and Zhao, Wei and Amin, Najaf and Arzumanyan, Zorayr and Astrup, Arne and Bakker, Stephan J L and Baldassarre, Damiano and Beekman, Marian and Bergman, Richard N and Bertoni, Alain and Bl{\"u}her, Matthias and Bonnycastle, Lori L and Bornstein, Stefan R and Bowden, Donald W and Cai, Qiuyin and Campbell, Archie and Campbell, Harry and Chang, Yi Cheng and de Geus, Eco J C and Dehghan, Abbas and Du, Shufa and Eiriksdottir, Gudny and Farmaki, Aliki Eleni and Fr\aanberg, Mattias and Fuchsberger, Christian and Gao, Yutang and Gjesing, Anette P and Goel, Anuj and Han, Sohee and Hartman, Catharina A and Herder, Christian and Hicks, Andrew A and Hsieh, Chang-Hsun and Hsueh, Willa A and Ichihara, Sahoko and Igase, Michiya and Ikram, M Arfan and Johnson, W Craig and J{\o}rgensen, Marit E and Joshi, Peter K and Kalyani, Rita R and Kandeel, Fouad R and Katsuya, Tomohiro and Khor, Chiea Chuen and Kiess, Wieland and Kolcic, Ivana and Kuulasmaa, Teemu and Kuusisto, Johanna and L{\"a}ll, Kristi and Lam, Kelvin and Lawlor, Deborah A and Lee, Nanette R and Lemaitre, Rozenn N and Li, Honglan and Lifelines Cohort Study and Lin, Shih-Yi and Lindstr{\"o}m, Jaana and Linneberg, Allan and Liu, Jianjun and Lorenzo, Carlos and Matsubara, Tatsuaki and Matsuda, Fumihiko and Mingrone, Geltrude and Mooijaart, Simon and Moon, Sanghoon and Nabika, Toru and Nadkarni, Girish N and Nadler, Jerry L and Nelis, Mari and Neville, Matt J and Norris, Jill M and Ohyagi, Yasumasa and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Qi, Qibin and Raven, Dennis and Reilly, Dermot F and Reiner, Alex and Rivideneira, Fernando and Roll, Kathryn and Rudan, Igor and Sabanayagam, Charumathi and Sandow, Kevin and Sattar, Naveed and Sch{\"u}rmann, Annette and Shi, Jinxiu and Stringham, Heather M and Taylor, Kent D and Teslovich, Tanya M and Thuesen, Betina and Timmers, Paul R H J and Tremoli, Elena and Tsai, Michael Y and Uitterlinden, Andre and van Dam, Rob M and van Heemst, Diana and van Hylckama Vlieg, Astrid and van Vliet-Ostaptchouk, Jana V and Vangipurapu, Jagadish and Vestergaard, Henrik and Wang, Tao and Willems van Dijk, Ko and Zemunik, Tatijana and Abecasis, Gon\c calo R and Adair, Linda S and Aguilar-Salinas, Carlos Alberto and Alarc{\'o}n-Riquelme, Marta E and An, Ping and Aviles-Santa, Larissa and Becker, Diane M and Beilin, Lawrence J and Bergmann, Sven and Bisgaard, Hans and Black, Corri and Boehnke, Michael and Boerwinkle, Eric and B{\"o}hm, Bernhard O and B{\o}nnelykke, Klaus and Boomsma, D I and Bottinger, Erwin P and Buchanan, Thomas A and Canouil, Micka{\"e}l and Caulfield, Mark J and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Cheng, Ching-Yu and Collins, Francis S and Correa, Adolfo and Cucca, Francesco and de Silva, H Janaka and Dedoussis, George and Elmst\aahl, S{\"o}lve and Evans, Michele K and Ferrannini, Ele and Ferrucci, Luigi and Florez, Jose C and Franks, Paul W and Frayling, Timothy M and Froguel, Philippe and Gigante, Bruna and Goodarzi, Mark O and Gordon-Larsen, Penny and Grallert, Harald and Grarup, Niels and Grimsgaard, Sameline and Groop, Leif and Gudnason, Vilmundur and Guo, Xiuqing and Hamsten, Anders and Hansen, Torben and Hayward, Caroline and Heckbert, Susan R and Horta, Bernardo L and Huang, Wei and Ingelsson, Erik and James, Pankow S and Jarvelin, Marjo-Ritta and Jonas, Jost B and Jukema, J Wouter and Kaleebu, Pontiano and Kaplan, Robert and Kardia, Sharon L R and Kato, Norihiro and Keinanen-Kiukaanniemi, Sirkka M and Kim, Bong-Jo and Kivimaki, Mika and Koistinen, Heikki A and Kooner, Jaspal S and K{\"o}rner, Antje and Kovacs, Peter and Kuh, Diana and Kumari, Meena and Kutalik, Zoltan and Laakso, Markku and Lakka, Timo A and Launer, Lenore J and Leander, Karin and Li, Huaixing and Lin, Xu and Lind, Lars and Lindgren, Cecilia and Liu, Simin and Loos, Ruth J F and Magnusson, Patrik K E and Mahajan, Anubha and Metspalu, Andres and Mook-Kanamori, Dennis O and Mori, Trevor A and Munroe, Patricia B and Nj{\o}lstad, Inger and O{\textquoteright}Connell, Jeffrey R and Oldehinkel, Albertine J and Ong, Ken K and Padmanabhan, Sandosh and Palmer, Colin N A and Palmer, Nicholette D and Pedersen, Oluf and Pennell, Craig E and Porteous, David J and Pramstaller, Peter P and Province, Michael A and Psaty, Bruce M and Qi, Lu and Raffel, Leslie J and Rauramaa, Rainer and Redline, Susan and Ridker, Paul M and Rosendaal, Frits R and Saaristo, Timo E and Sandhu, Manjinder and Saramies, Jouko and Schneiderman, Neil and Schwarz, Peter and Scott, Laura J and Selvin, Elizabeth and Sever, Peter and Shu, Xiao-Ou and Slagboom, P Eline and Small, Kerrin S and Smith, Blair H and Snieder, Harold and Sofer, Tamar and S{\o}rensen, Thorkild I A and Spector, Tim D and Stanton, Alice and Steves, Claire J and Stumvoll, Michael and Sun, Liang and Tabara, Yasuharu and Tai, E Shyong and Timpson, Nicholas J and T{\"o}njes, Anke and Tuomilehto, Jaakko and Tusie, Teresa and Uusitupa, Matti and van der Harst, Pim and van Duijn, Cornelia and Vitart, Veronique and Vollenweider, Peter and Vrijkotte, Tanja G M and Wagenknecht, Lynne E and Walker, Mark and Wang, Ya X and Wareham, Nick J and Watanabe, Richard M and Watkins, Hugh and Wei, Wen B and Wickremasinghe, Ananda R and Willemsen, Gonneke and Wilson, James F and Wong, Tien-Yin and Wu, Jer-Yuarn and Xiang, Anny H and Yanek, Lisa R and Yengo, Lo\"{\i}c and Yokota, Mitsuhiro and Zeggini, Eleftheria and Zheng, Wei and Zonderman, Alan B and Rotter, Jerome I and Gloyn, Anna L and McCarthy, Mark I and Dupuis, Jos{\'e}e and Meigs, James B and Scott, Robert A and Prokopenko, Inga and Leong, Aaron and Liu, Ching-Ti and Parker, Stephen C J and Mohlke, Karen L and Langenberg, Claudia and Wheeler, Eleanor and Morris, Andrew P and Barroso, In{\^e}s and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)} } @article {332, title = {The (broad-sense) genetic correlations among four measures of inattention and hyperactivity in 12 year Olds}, journal = {Behavior Genetics}, volume = {50}, year = {2020}, pages = {273{\textendash}288}, abstract = {

We estimated the genetic covariance matrix among four inattention (INATT) and four hyperactivity (HYP) measures in the classical twin design. Data on INATT and HYP symptom counts were obtained in mono- and dizygotic twin pairs (N = 1593) with an average age of 12.2 years (sd = .51). We analyzed maternal ratings of INATT and HYP based on the Conners\&$\#$39; Parent Rating Scale (CPRS), the Strengths and Weaknesses of ADHD-symptoms and Normal-behavior (SWAN), and teacher ratings based on the Conners\&$\#$39; Teacher rating scale (CTRS) and the ASEBA Teacher Rating Form (TRF). Broad-sense heritabilities, corrected for the main effects of sex and for random teacher rater effects, were large (ranging from .658 to .912). The results reveal pervasive and strong broad-sense genetic effects on INATT and HYP phenotypes with the phenotypic covariance among the phenotypes largely due to correlated genetic effects. Specifically between 79.9 and 99.9\% of the phenotypic covariance among the HYP measures, and between 81.0 and 93.5\% of the INATT measures are attributable to broad-sense genetic effects. Overall, the present results, pertaining to the broad-sense heritabilities and shared genetic effects, support the current genome-wide association meta-analytic approach to identifying pleiotropic genetic variants.

}, keywords = {ADHD, Genetic correlation, Hyperactivity, Inattention, Multivariate genetic model, Twin design}, doi = {10.1007/s10519-020-10002-2}, author = {Dolan, Conor V and de Zeeuw, Eveline L and Zayats, Tetyana and van Beijsterveldt, C E M and Boomsma, Dorret I} } @article {336, title = {Comparing the genetic architecture of childhood behavioral problems across socioeconomic strata in the Netherlands and the United Kingdom}, journal = {European Child \& Adolescent Psychiatry}, volume = {29}, year = {2020}, pages = {353{\textendash}362}, abstract = {

Socioeconomic status (SES) affects the development of childhood behavioral problems. It has been frequently observed that children from low SES background tend to show more behavioral problems. There also is some evidence that SES has a moderating effect on the causes of individual differences in childhood behavioral problems, with lower heritability estimates and a stronger contribution of environmental factors in low SES groups. The aim of the present study was to examine whether the genetic architecture of childhood behavioral problems suggests the presence of protective and/or harmful effects across socioeconomic strata, in two countries with different levels of socioeconomic disparity: the Netherlands and the United Kingdom. We analyzed data from 7-year-old twins from the Netherlands Twin Register (N = 24,112 twins) and the Twins Early Development Study (N = 19,644 twins). The results revealed a nonlinear moderation effect of SES on the contribution of genetic and environmental factors to individual differences in childhood behavioral problems. The heritability was higher, the contribution of the shared environment was lower, and the contribution of the nonshared environment was higher, for children from high SES families, compared to children from low or medium SES families. The pattern was similar for Dutch and UK families. We discuss the importance of these findings for prevention and intervention goals.

}, keywords = {Childhood behavioral problems, Netherlands, Socioeconomic status, UK}, doi = {10.1007/s00787-019-01357-x}, author = {Hendriks, A M and Finkenauer, C and Nivard, M G and van Beijsterveldt, C E M and Plomin, R J and Boomsma, D I and Bartels, M} } @article {388, title = {Content, diagnostic, correlational, and genetic similarities between common measures of childhood aggressive behaviors and related psychiatric traits}, journal = {Journal of Child Psychology and Psychiatry}, volume = {61}, year = {2020}, pages = {1328-1338}, abstract = {

Background Given the role of childhood aggressive behavior (AGG) in everyday child development, precise and accurate measurement is critical in clinical practice and research. This study aims to quantify agreement among widely used measures of childhood AGG regarding item content, clinical concordance, correlation, and underlying genetic construct. Methods We analyzed data from 1254 Dutch twin pairs (age 8{\^a}\€\“10{\^A}\ years, 51.1\% boys) from a general population sample for whom both parents completed the A-TAC, CBCL, and SDQ at the same occasion. Results There was substantial variation in item content among AGG measures, ranging from .00 (i.e., mutually exclusive) to .50 (moderate agreement). Clinical concordance (i.e., do the same children score above a clinical threshold among AGG measures) was very weak to moderate with estimates ranging between .01 and .43 for mother-reports and between .12 and .42 for father-reports. Correlations among scales were weak to strong, ranging from .32 to .70 for mother-reports and from .32 to .64 for father-reports. We found weak to very strong genetic correlations among the measures, with estimates between .65 and .84 for mother-reports and between .30 and .87 for father-reports. Conclusions Our results demonstrated that degree of agreement between measures of AGG depends on the type (i.e., item content, clinical concordance, correlation, genetic correlation) of agreement considered. Because agreement was higher for correlations compared to clinical concordance (i.e., above or below a clinical cutoff), we propose the use of continuous scores to assess AGG, especially for combining data with different measures. Although item content can be different and agreement among observed measures may not be high, the genetic correlations indicate that the underlying genetic liability for childhood AGG is consistent across measures.

}, keywords = {Childhood aggressive behavior, clinical concordance, Genetic correlation, item overlap}, doi = {https://doi.org/10.1111/jcpp.13218}, url = {https://acamh.onlinelibrary.wiley.com/doi/abs/10.1111/jcpp.13218}, author = {Hendriks, Anne M. and Ip, Hill F. and Nivard, Michel G. and Finkenauer, Catrin and Van Beijsterveldt, Catharina E.M. and Bartels, Meike and Boomsma, Dorret I.} } @article {342, title = {An extended twin-pedigree study of different classes of voluntary exercise behavior}, journal = {Behavior Genetics}, volume = {50}, year = {2020}, pages = {94{\textendash}104}, abstract = {

We investigated the familial clustering of different classes of voluntary regular exercise behavior in extended twin-family pedigrees. In contrast to the earlier work based on twin data only, this allowed us to estimate the contributions of shared household effects (C), additive (A), and non-additive (D) genetic effects on voluntary exercise behavior. To test whether shared household effects were inflated by assortative mating we examined the causes of spousal resemblance. For adolescent and adult participants (aged 16 to 65) in the Netherlands Twin Register we constructed 19,543 pedigrees which specified all relations among nuclear family members and larger families in the register (N = 50,690 individuals). Data were available on total weekly MET minutes spent on leisure time exercise, and on total weekly MET minutes spent on exercise activities in team-based, solitary, competitive, non-competitive, externally paced and internally paced exercise. We analyzed the data in the Mendel software package (Lange et al. in Bioinformatics 29(12):1568-1570, 2013) under multiple definitions of household sharing and used data from spouses of twins to test phenotypic assortment, social homogamy, and marital interaction as potential sources of spousal resemblance. Results confirmed the influence of genetic factors on the total volume of weekly exercise behavior throughout the life span. Broad sense heritability ranged from 34 to 41\% (19-26\% A, 12-21\% D), and did not depend on the definition for household sharing. Engaging in team-based, competitive, externally paced activities (e.g., soccer) was \  13\% more heritable than engaging in non-competitive, solitary activities (e.g., jogging). Having shared a household as siblings explained 4-8\% of the variance in adult exercise behavior, whereas sharing a household by spouses yielded higher C estimates (20-24\%), as it incorporates spousal resemblance. Spousal resemblance was explained by both social homogamy and marital interaction, with little evidence for phenotypic assortment. We conclude that both the amount of voluntary exercise behavior and the preference for specific classes of exercise activities in adults is explained by additive and non-additive genetic factors and unique environmental influences that include correlated exercise behavior of spouses.

}, keywords = {Exercise behavior, heritability, Household, Pedigree, Spousal resemblance, twins}, doi = {10.1007/s10519-019-09990-7}, author = {van der Zee, Matthijs D and Helmer, Q and Boomsma, D I and Dolan, C V and de Geus, E J C} } @article {333, title = {The genetic architecture of the human cerebral cortex}, journal = {Science}, volume = {367}, year = {2020}, pages = {eaay6690}, abstract = {

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson\&$\#$39;s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

}, doi = {10.1126/science.aay6690}, author = {Grasby, Katrina L and Jahanshad, Neda and Painter, Jodie N and Colodro-Conde, Luc{\'\i}a and Bralten, Janita and Hibar, Derrek P and Lind, Penelope A and Pizzagalli, Fabrizio and Ching, Christopher R K and McMahon, Mary Agnes B and Shatokhina, Natalia and Zsembik, Leo C P and Thomopoulos, Sophia I and Zhu, Alyssa H and Strike, Lachlan T and Agartz, Ingrid and Alhusaini, Saud and Almeida, Marcio A A and Aln{\ae}s, Dag and Amlien, Inge K and Andersson, Micael and Ard, Tyler and Armstrong, Nicola J and Ashley-Koch, Allison and Atkins, Joshua R and Bernard, Manon and Brouwer, Rachel M and Buimer, Elizabeth E L and B{\"u}low, Robin and B{\"u}rger, Christian and Cannon, Dara M and Chakravarty, Mallar and Chen, Qiang and Cheung, Joshua W and Couvy-Duchesne, Baptiste and Dale, Anders M and Dalvie, Shareefa and de Araujo, T{\^a}nia K and de Zubicaray, Greig I and de Zwarte, Sonja M C and den Braber, Anouk and Doan, Nhat Trung and Dohm, Katharina and Ehrlich, Stefan and Engelbrecht, Hannah-Ruth and Erk, Susanne and Fan, Chun Chieh and Fedko, Iryna O and Foley, Sonya F and Ford, Judith M and Fukunaga, Masaki and Garrett, Melanie E and Ge, Tian and Giddaluru, Sudheer and Goldman, Aaron L and Green, Melissa J and Groenewold, Nynke A and Grotegerd, Dominik and Gurholt, Tiril P and Gutman, Boris A and Hansell, Narelle K and Harris, Mathew A and Harrison, Marc B and Haswell, Courtney C and Hauser, Michael and Herms, Stefan and Heslenfeld, Dirk J and Ho, New Fei and Hoehn, David and Hoffmann, Per and Holleran, Laurena and Hoogman, Martine and Hottenga, Jouke-Jan and Ikeda, Masashi and Janowitz, Deborah and Jansen, Iris E and Jia, Tianye and Jockwitz, Christiane and Kanai, Ryota and Karama, Sherif and Kasperaviciute, Dalia and Kaufmann, Tobias and Kelly, Sinead and Kikuchi, Masataka and Klein, Marieke and Knapp, Michael and Knodt, Annchen R and Kr{\"a}mer, Bernd and Lam, Max and Lancaster, Thomas M and Lee, Phil H and Lett, Tristram A and Lewis, Lindsay B and Lopes-Cendes, Iscia and Luciano, Michelle and Macciardi, Fabio and Marquand, Andre F and Mathias, Samuel R and Melzer, Tracy R and Milaneschi, Yuri and Mirza-Schreiber, Nazanin and Moreira, Jose C V and M{\"u}hleisen, Thomas W and M{\"u}ller-Myhsok, Bertram and Najt, Pablo and Nakahara, Soichiro and Nho, Kwangsik and Olde Loohuis, Loes M and Orfanos, Dimitri Papadopoulos and Pearson, John F and Pitcher, Toni L and P{\"u}tz, Benno and Quid{\'e}, Yann and Ragothaman, Anjanibhargavi and Rashid, Faisal M and Reay, William R and Redlich, Ronny and Reinbold, C{\'e}line S and Repple, Jonathan and Richard, Genevi{\`e}ve and Riedel, Brandalyn C and Risacher, Shannon L and Rocha, Cristiane S and Mota, Nina Roth and Salminen, Lauren and Saremi, Arvin and Saykin, Andrew J and Schlag, Fenja and Schmaal, Lianne and Schofield, Peter R and Secolin, Rodrigo and Shapland, Chin Yang and Shen, Li and Shin, Jean and Shumskaya, Elena and S{\o}nderby, Ida E and Sprooten, Emma and Tansey, Katherine E and Teumer, Alexander and Thalamuthu, Anbupalam and Tordesillas-Guti{\'e}rrez, Diana and Turner, Jessica A and Uhlmann, Anne and Vallerga, Costanza Ludovica and van der Meer, Dennis and van Donkelaar, Marjolein M J and van Eijk, Liza and van Erp, Theo G M and van Haren, Neeltje E M and van Rooij, Daan and van Tol, Marie-Jos{\'e} and Veldink, Jan H and Verhoef, Ellen and Walton, Esther and Wang, Mingyuan and Wang, Yunpeng and Wardlaw, Joanna M and Wen, Wei and Westlye, Lars T and Whelan, Christopher D and Witt, Stephanie H and Wittfeld, Katharina and Wolf, Christiane and Wolfers, Thomas and Wu, Jing Qin and Yasuda, Clarissa L and Zaremba, Dario and Zhang, Zuo and Zwiers, Marcel P and Artiges, Eric and Assareh, Amelia A and Ayesa-Arriola, Rosa and Belger, Aysenil and Brandt, Christine L and Brown, Gregory G and Cichon, Sven and Curran, Joanne E and Davies, Gareth E and Degenhardt, Franziska and Dennis, Michelle F and Dietsche, Bruno and Djurovic, Srdjan and Doherty, Colin P and Espiritu, Ryan and Garijo, Daniel and Gil, Yolanda and Gowland, Penny A and Green, Robert C and H{\"a}usler, Alexander N and Heindel, Walter and Ho, Beng-Choon and Hoffmann, Wolfgang U and Holsboer, Florian and Homuth, Georg and Hosten, Norbert and Jack, Jr, Clifford R and Jang, Mihyun and Jansen, Andreas and Kimbrel, Nathan A and Kolsk\aar, Knut and Koops, Sanne and Krug, Axel and Lim, Kelvin O and Luykx, Jurjen J and Mathalon, Daniel H and Mather, Karen A and Mattay, Venkata S and Matthews, Sarah and Mayoral Van Son, Jaqueline and McEwen, Sarah C and Melle, Ingrid and Morris, Derek W and Mueller, Bryon A and Nauck, Matthias and Nordvik, Jan E and N{\"o}then, Markus M and O{\textquoteright}Leary, Daniel S and Opel, Nils and Martinot, Marie-Laure Paill{\`e}re and Pike, G Bruce and Preda, Adrian and Quinlan, Erin B and Rasser, Paul E and Ratnakar, Varun and Reppermund, Simone and Steen, Vidar M and Tooney, Paul A and Torres, F{\'a}bio R and Veltman, Dick J and Voyvodic, James T and Whelan, Robert and White, Tonya and Yamamori, Hidenaga and Adams, Hieab H H and Bis, Joshua C and Debette, Stephanie and Decarli, Charles and Fornage, Myriam and Gudnason, Vilmundur and Hofer, Edith and Ikram, M Arfan and Launer, Lenore and Longstreth, W T and Lopez, Oscar L and Mazoyer, Bernard and Mosley, Thomas H and Roshchupkin, Gennady V and Satizabal, Claudia L and Schmidt, Reinhold and Seshadri, Sudha and Yang, Qiong and Alzheimer{\textquoteright}s Disease Neuroimaging Initiative and CHARGE Consortium and EPIGEN Consortium and IMAGEN Consortium and SYS Consortium and Parkinson{\textquoteright}s Progression Markers Initiative and Alvim, Marina K M and Ames, David and Anderson, Tim J and Andreassen, Ole A and Arias-Vasquez, Alejandro and Bastin, Mark E and Baune, Bernhard T and Beckham, Jean C and Blangero, John and Boomsma, Dorret I and Brodaty, Henry and Brunner, Han G and Buckner, Randy L and Buitelaar, Jan K and Bustillo, Juan R and Cahn, Wiepke and Cairns, Murray J and Calhoun, Vince and Carr, Vaughan J and Caseras, Xavier and Caspers, Svenja and Cavalleri, Gianpiero L and Cendes, Fernando and Corvin, Aiden and Crespo-Facorro, Benedicto and Dalrymple-Alford, John C and Dannlowski, Udo and de Geus, Eco J C and Deary, Ian J and Delanty, Norman and Depondt, Chantal and Desrivi{\`e}res, Sylvane and Donohoe, Gary and Espeseth, Thomas and Fern{\'a}ndez, Guill{\'e}n and Fisher, Simon E and Flor, Herta and Forstner, Andreas J and Francks, Clyde and Franke, Barbara and Glahn, David C and Gollub, Randy L and Grabe, Hans J and Gruber, Oliver and H\aaberg, Asta K and Hariri, Ahmad R and Hartman, Catharina A and Hashimoto, Ryota and Heinz, Andreas and Henskens, Frans A and Hillegers, Manon H J and Hoekstra, Pieter J and Holmes, Avram J and Hong, L Elliot and Hopkins, William D and Hulshoff Pol, Hilleke E and Jernigan, Terry L and J{\"o}nsson, Erik G and Kahn, Ren{\'e} S and Kennedy, Martin A and Kircher, Tilo T J and Kochunov, Peter and Kwok, John B J and Le Hellard, Stephanie and Loughland, Carmel M and Martin, Nicholas G and Martinot, Jean-Luc and McDonald, Colm and McMahon, Katie L and Meyer-Lindenberg, Andreas and Michie, Patricia T and Morey, Rajendra A and Mowry, Bryan and Nyberg, Lars and Oosterlaan, Jaap and Ophoff, Roel A and Pantelis, Christos and Paus, Tomas and Pausova, Zdenka and Penninx, Brenda W J H and Polderman, Tinca J C and Posthuma, Danielle and Rietschel, Marcella and Roffman, Joshua L and Rowland, Laura M and Sachdev, Perminder S and S{\"a}mann, Philipp G and Schall, Ulrich and Schumann, Gunter and Scott, Rodney J and Sim, Kang and Sisodiya, Sanjay M and Smoller, Jordan W and Sommer, Iris E and St Pourcain, Beate and Stein, Dan J and Toga, Arthur W and Trollor, Julian N and Van der Wee, Nic J A and van {\textquoteright}t Ent, Dennis and V{\"o}lzke, Henry and Walter, Henrik and Weber, Bernd and Weinberger, Daniel R and Wright, Margaret J and Zhou, Juan and Stein, Jason L and Thompson, Paul M and Medland, Sarah E and Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)-Genetics working group} } @article {339, title = {Genetics and not shared environment explains familial resemblance in adult metabolomics data}, journal = {Twin Research and Human Genetics}, volume = {23}, year = {2020}, pages = {145{\textendash}155}, abstract = {

Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term \&$\#$39;metabolomics\&$\#$39; refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.

}, keywords = {classical twin design, enrichment analysis, heritability, metabolite classes, shared environment}, doi = {10.1017/thg.2020.53}, author = {Pool, Ren{\'e} and Hagenbeek, Fiona A and Hendriks, Anne M and van Dongen, Jenny and Willemsen, Gonneke and de Geus, Eco and BBMRI Metabolomics Consortium and Willems van Dijk, Ko and Verhoeven, Aswin and Suchiman, H Eka and Beekman, Marian and Slagboom, P Eline and Harms, Amy C and Hankemeier, Thomas and Boomsma, Dorret I} } @article {338, title = {Harmonizing behavioral outcomes across studies, raters, and countries: application to the genetic analysis of aggression in the ACTION Consortium}, journal = {Journal of Child Psychology and Psychiatry}, volume = {61}, year = {2020}, pages = {807{\textendash}817}, abstract = {

BACKGROUND: Aggression in children has genetic and environmental causes. Studies of aggression can pool existing datasets to include more complex models of social effects. Such analyses require large datasets with harmonized outcome measures. Here, we made use of a reference panel for phenotype data to harmonize multiple aggression measures in school-aged children to jointly analyze data from five large twin cohorts. METHODS: Individual level aggression data on 86,559 children (42,468 twin pairs) were available in five European twin cohorts measured by different instruments. A phenotypic reference panel was collected which enabled a model-based phenotype harmonization approach. A bi-factor integration model in the integrative data analysis framework was developed to model aggression across studies while adjusting for rater, age, and sex. Finally, harmonized aggression scores were analyzed to estimate contributions of genes, environment, and social interaction to aggression. The large sample size allowed adequate power to test for sibling interaction effects, with unique dynamics permitted for opposite-sex twins. RESULTS: The best-fitting model found a high level of overall heritability of aggression (\ 60\%). Different heritability rates of aggression across sex were marginally significant, with heritability estimates in boys of \ 64\% and \ 58\% in girls. Sibling interaction effects were only significant in the opposite-sex twin pairs: the interaction effect of males on their female co-twin differed from the effect of females on their male co-twin. An aggressive female had a positive effect on male co-twin aggression, whereas more aggression in males had a negative influence on a female co-twin. CONCLUSIONS: Opposite-sex twins displayed unique social dynamics of aggressive behaviors in a joint analysis of a large, multinational dataset. The integrative data analysis framework, applied in combination with a reference panel, has the potential to elucidate broad, generalizable results in the investigation of common psychological traits in children.

}, keywords = {Aggression, developmental psychopathology, integrative data analysis, phenotype reference panel, twin modeling}, doi = {10.1111/jcpp.13188}, author = {Luningham, Justin M and Hendriks, Anne M and Krapohl, Eva and Fung Ip, Hill and van Beijsterveldt, Catharina E M and Lundstr{\"o}m, Sebastian and Vuoksimaa, Eero and Korhonen, Tellervo and Lichtenstein, Paul and Plomin, Robert and Pulkkinen, Lea and Rose, Richard J and Kaprio, Jaakko and Bartels, Meike and Boomsma, Dorret I and Lubke, Gitta H} } @article {335, title = {Heritability estimates for 361 blood metabolites across 40 genome-wide association studies}, journal = {Nature Communications}, volume = {11}, year = {2020}, pages = {39}, abstract = {

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50\% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify \>800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2total), and the proportion of heritability captured by known metabolite loci (h2Metabolite-hits) for 309 lipids and 52 organic acids. Our study reveals significant differences in h2Metabolite-hits among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation have higher h2Metabolite-hits estimates than phosphatidylcholines with low degrees of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes.

}, doi = {10.1038/s41467-019-13770-6}, author = {Hagenbeek, Fiona A and Pool, Ren{\'e} and van Dongen, Jenny and Draisma, Harmen H M and Jan Hottenga, Jouke and Willemsen, Gonneke and Abdellaoui, Abdel and Fedko, Iryna O and den Braber, Anouk and Visser, Pieter Jelle and de Geus, Eco J C N and Willems van Dijk, Ko and Verhoeven, Aswin and Suchiman, H Eka and Beekman, Marian and Slagboom, P Eline and van Duijn, Cornelia M and BBMRI Metabolomics Consortium and Harms, Amy C and Hankemeier, Thomas and Bartels, Meike and Nivard, Michel G and Boomsma, Dorret I} } @article {337, title = {Identification, heritability, and relation with gene expression of novel DNA methylation loci for blood pressure}, journal = {Hypertension}, volume = {76}, year = {2020}, pages = {195{\textendash}205}, abstract = {

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P\<1$\times$10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P\<1$\times$10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P\<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61\% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84\% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100\% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.

}, keywords = {blood pressure, DNA methylation, epigenome, hypertension, twin study}, doi = {10.1161/HYPERTENSIONAHA.120.14973}, author = {Huang, Yisong and Ollikainen, Miina and Muniandy, Maheswary and Zhang, Tao and van Dongen, Jenny and Hao, Guang and van der Most, Peter J and Pan, Yue and Pervjakova, Natalia and Sun, Yan V and Hui, Qin and Lahti, Jari and Fraszczyk, Eliza and Lu, Xueling and Sun, Dianjianyi and Richard, Melissa A and Willemsen, Gonneke and Heikkil{\"a}, Kauko and Mateo Leach, Irene and Mononen, Nina and K{\"a}h{\"o}nen, Mika and Hurme, Mikko A and Raitakari, Olli T and Drake, Amanda J and Perola, Markus and Nuotio, Marja-Liisa and Huang, Yunfeng and Khulan, Batbayar and R{\"a}ikk{\"o}nen, Katri and Wolffenbuttel, Bruce H R and Zhernakova, Alexandra and Fu, Jingyuan and Zhu, Haidong and Dong, Yanbin and van Vliet-Ostaptchouk, Jana V and Franke, Lude and Eriksson, Johan G and Fornage, Myriam and Milani, Lili and Lehtim{\"a}ki, Terho and Vaccarino, Viola and Boomsma, Dorret I and van der Harst, Pim and de Geus, Eco J C and Salomaa, Veikko and Li, Shengxu and Chen, Wei and Su, Shaoyong and Wilson, James and Snieder, Harold and Kaprio, Jaakko and Wang, Xiaoling} } @article {352, title = {Measurement and genetic architecture of lifetime depression in the Netherlands as assessed by LIDAS (Lifetime Depression Assessment Self-report)}, journal = {Psychological Medicine}, volume = {51}, year = {2020}, pages = {1{\textendash}10}, abstract = {

BACKGROUND: Major depressive disorder (MDD) is a common mood disorder, with a heritability of around 34\%. Molecular genetic studies made significant progress and identified genetic markers associated with the risk of MDD; however, progress is slowed down by substantial heterogeneity as MDD is assessed differently across international cohorts. Here, we used a standardized online approach to measure MDD in multiple cohorts in the Netherlands and evaluated whether this approach can be used in epidemiological and genetic association studies of depression.

METHODS: Within the Biobank Netherlands Internet Collaboration (BIONIC) project, we collected MDD data in eight cohorts involving 31 936 participants, using the online Lifetime Depression Assessment Self-report (LIDAS), and estimated the prevalence of current and lifetime MDD in 22 623 unrelated individuals. In a large Netherlands Twin Register (NTR) twin-family dataset (n $\approx$ 18 000), we estimated the heritability of MDD, and the prediction of MDD in a subset (n = 4782) through Polygenic Risk Score (PRS).

RESULTS: Estimates of current and lifetime MDD prevalence were 6.7\% and 18.1\%, respectively, in line with population estimates based on validated psychiatric interviews. In the NTR heritability estimates were 0.34/0.30 (s.e. = 0.02/0.02) for current/lifetime MDD, respectively, showing that the LIDAS gives similar heritability rates for MDD as reported in the literature. The PRS predicted risk of MDD (OR 1.23, 95\% CI 1.15-1.3

}, keywords = {LIDAS, Lifetime Depression Assessment Self-report, major depressive disorder, online assessment tool, prevalence}, doi = {10.1017/S0033291720000100}, author = {Fedko, Iryna O and Hottenga, Jouke-Jan and Helmer, Quinta and Mbarek, Hamdi and Huider, Floris and Amin, Najaf and Beulens, Joline W and Bremmer, Marijke A and Elders, Petra J and Galesloot, Tessel E and Kiemeney, Lambertus A and van Loo, Hanna M and Picavet, H Susan J and Rutters, Femke and van der Spek, Ashley and van de Wiel, Anne M and van Duijn, Cornelia and de Geus, Eco J C and Feskens, Edith J M and Hartman, Catharina A and Oldehinkel, Albertine J and Smit, Jan H and Verschuren, W M Monique and Penninx, Brenda W J H and Boomsma, Dorret I and Bot, Mariska} } @article {341, title = {Out of control: Examining the association between family conflict and self-control in adolescence in a genetically sensitive design}, journal = {Journal of the American Academy of Child \& Adolescent Psychiatry}, volume = {59}, year = {2020}, pages = {254{\textendash}262}, abstract = {

OBJECTIVE: Family conflict is associated with low self-control in adolescence. Thus far research about the direction of this association is inconclusive. In this study, we sort out whether this association reflects a causal effect or whether it is explained by a common underlying cause, including genetic factors.

METHOD: In twin data, we fitted a series of causal models, and compared models for the association of family conflict and self-control including reciprocal causation, unidirectional causation from family conflict to low self-control, unidirectional causation from low self-control to family conflict, and common genetic susceptibility. We included data from a large sample of twins aged 14 years (N = 9,173), all enrolled in the Netherlands Twin Register.

RESULTS: The results suggested a unidirectional pathway model in which family conflict leads to low self-control in adolescence, with genetic factors also playing a role in explaining the association.

CONCLUSION: Adolescents experiencing family conflict are at risk for showing hampered self-control capacities, with family conflict being a robust predictor of low self-control through common genetic factors but also through direct causal influences.

}, keywords = {environment, family conflict, genetics, self-control, twins}, doi = {10.1016/j.jaac.2019.02.017}, author = {Willems, Yayouk E and de Zeeuw, Eveline L and van Beijsterveldt, Catharina E M and Boomsma, Dorret I and Bartels, Meike and Finkenauer, Catrin} } @article {343, title = {Parental age and offspring childhood mental health: A multi-cohort, population-based investigation}, journal = {Child Development}, volume = {91}, year = {2020}, pages = {964{\textendash}982}, abstract = {

To examine the contributions of maternal and paternal age on offspring externalizing and internalizing problems, this study analyzed problem behaviors at age 10-12 years from four Dutch population-based cohorts (N = 32,892) by a multiple informant design. Bayesian evidence synthesis was used to combine results across cohorts with 50\% of the data analyzed for discovery and 50\% for confirmation. There was evidence of a robust negative linear relation between parental age and externalizing problems as reported by parents. In teacher-reports, this relation was largely explained by parental socio-economic status. Parental age had limited to no association with internalizing problems. Thus, in this large population-based study, either a beneficial or no effect of advanced parenthood on child problem behavior was observed.

}, doi = { 10.1111/cdev.13267}, author = {Zondervan-Zwijnenburg, Maria A J and Veldkamp, Sabine A M and Neumann, Alexander and Barzeva, Stefania A and Nelemans, Stefanie A and van Beijsterveldt, Catharina E M and Branje, Susan J T and Hillegers, Manon H J and Meeus, Wim H J and Tiemeier, Henning and Hoijtink, Herbert J A and Oldehinkel, Albertine J and Boomsma, Dorret I} } @article {334, title = {Urinary Amine and organic acid metabolites evaluated as markers for childhood aggression: The ACTION biomarker study}, journal = {Frontiers in Psychiatry}, volume = {11}, year = {2020}, pages = {165}, abstract = {

Biomarkers are of interest as potential diagnostic and predictive instruments in personalized medicine. We present the first urinary metabolomics biomarker study of childhood aggression. We aim to examine the association of urinary metabolites and neurotransmitter ratios involved in key metabolic and neurotransmitter pathways in a large cohort of twins (N = 1,347) and clinic-referred children (N = 183) with an average age of 9.7 years. This study is part of ACTION (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies), in which we developed a standardized protocol for large-scale collection of urine samples in children. Our analytical design consisted of three phases: a discovery phase in twins scoring low or high on aggression (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine ($\beta$ = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine ($\beta$ = 0.32; SE = 0.09; p = 0.01) remained significant after multiple testing. Although non-significant, the directions of effect were congruent between the discovery and replication analyses for six biomarkers and two neurotransmitter ratios and the concentrations of 6 amines differed between low and high aggressive twins. In the validation analyses, the top biomarkers and neurotransmitter ratios, with congruent directions of effect, showed no significant associations with childhood aggression. We find suggestive evidence for associations of childhood aggression with metabolic dysregulation of neurotransmission, oxidative stress, and energy metabolism. Although replication is required, our findings provide starting points to investigate causal and pleiotropic effects of these dysregulations on childhood aggression.

}, keywords = {amines, biomarkers, childhood aggression, metabolites, metabolomics, neurotransmitters, organic acids, oxidative stress}, doi = {10.3389/fpsyt.2020.00165}, author = {Hagenbeek, Fiona A and Roetman, Peter J and Pool, Ren{\'e} and Kluft, Cornelis and Harms, Amy C and van Dongen, Jenny and Colins, Olivier F and Talens, Simone and van Beijsterveldt, Catharina E M and Vandenbosch, Marjolein M L J Z and de Zeeuw, Eveline L and D{\'e}jean, S{\'e}bastien and Fanos, Vassilios and Ehli, Erik A and Davies, Gareth E and Hottenga, Jouke Jan and Hankemeier, Thomas and Bartels, Meike and Vermeiren, Robert R J M and Boomsma, Dorret I} } @article {289, title = {Awareness and perceptions of clinical guidelines for the diagnostics and treatment of severe behavioural problems in children across Europe: A qualitative survey with academic experts}, journal = {European PsychiatryEuropean Psychiatry}, volume = {57}, year = {2019}, month = {2019/04/01}, pages = {1 - 9}, abstract = {

Background
Severe behavioural problems (SBPs1) in childhood are highly prevalent, impair functioning, and predict negative outcomes later in life. Over the last decade, clinical practice guidelines for SBPs have been developed across Europe to facilitate the translation of scientific evidence into clinical practice. This study outlines the results of an investigation into academic experts\’ perspectives on the current prevalence, implementation, and utility of clinical guidelines for SBPs in children aged 6\–12 across Europe.

Methods
An online semi-structured questionnaire was completed by 28 psychiatry and psychology experts from 23 countries.

Results
Experts indicated that approximately two thirds of the included European countries use at least an unofficial clinical document such as textbooks, while nearly half possess official guidelines for SBPs. Experts believed that, although useful for practice, guidelines\’ benefits would be maximised if they included more specific recommendations and were implemented more conscientiously. Similarly, experts suggested that unofficial clinical documents offer a wide range of treatment options to individualise treatment from. However, they stressed the need for more consistent, evidence-based clinical practices, by means of developing national and European clinical guidelines for SBPs.

Conclusions
This study offers a preliminary insight into the current successes and challenges perceived by experts around Europe associated with guidelines and documents for SBPs, acting as a stepping stone for future systematic, in-depth investigations of guidelines. Additionally, it establishes experts\’ consensus for the need to develop official guidelines better tailored to clinical practice, creating a momentum for a transition towards European clinical guidelines for this population.

}, isbn = {0924-9338}, url = {https://doi.org/10.1016/j.eurpsy.2018.12.009}, author = {Gatej, Alexandra-Raluca and Lamers, Audri and van Domburgh, Lieke and Crone, Matty and Ogden, Terje and Rijo, Daniel and Aronen, Eeva and Barroso, Ricardo and Boomsma, Dorret I. and Vermeiren, Robert} } @article {325, title = {Biological insights into multiple birth: genetic findings from UK Biobank}, journal = {European Journal of Human Genetics}, volume = {27}, year = {2019}, pages = {970{\textendash}979}, abstract = {

The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. We performed a genome-wide association study (GWAS) in 8962 participants with Caucasian ancestry from UK Biobank who reported being part of a multiple birth, and 409,591 singleton controls. We replicated the association between FSHB, SMAD3 and twinning in the gene-based (but not SNP-based) test, which had been established in previous genome-wide association analyses in mothers with dizygotic twin offspring. Additionally, we report a novel genetic variant associated with multiple birth, rs428022 at 15q23 (p = 2.84 $\times$ 10-8) close to two genes: PIAS1 and SKOR1. Finally, we identified meaningful genetic correlations between being part of a multiple birth and other phenotypes (anthropometric traits, health-related traits, and fertility-related measures). The outcomes of this study provide important new insights into the genetic aetiology of multiple births and fertility, and open up novel directions for fertility and reproduction research.

}, doi = {10.1038/s41431-019-0355-z}, author = {Mbarek, Hamdi and van de Weijer, Margot P and van der Zee, Mathijs D and Ip, Hill F and Beck, Jeffrey J and Abdellaoui, Abdel and Ehli, Erik A and Davies, Gareth E and Baselmans, Bart M L and Nivard, Michel G and Bartels, Meike and de Geus, Eco J and Boomsma, Dorret I} } @article {294, title = {Children With Early-Onset Disruptive Behavior: Parental Mental Disorders Predict Poor Psychosocial Functioning in Adolescence}, journal = {Journal of the American Academy of Child \& Adolescent Psychiatry}, year = {2019}, abstract = {

Objective
Parental mental disorders (MD) and child early-onset disruptive behavior (DB) are well-established risk factors for poor outcomes in adolescence. However, it is not clear whether parental MD increases risk of future maladjustment among children who already display DB.

Method
Parents of 9-year-old children reported on child DB, while a patient registry was used to determine parental MD. At follow-ups at 15 (N = 6319) and 18 years (N = 3068) information about various problems were collected via registries, parent- and, self-reports.

Results
In the total sample, child DB was related to all outcomes (mean odds ratio [OR] = 1.18; range = 1.07-1.51; ps \< .01), paternal MD to criminality, aggression, truancy, poor school performance, and a cumulative risk index of poor functioning, and maternal MD to peer problems, rule-breaking, and truancy (mean OR = 1.67; range = 1.19-2.71; ps \< .05). In the subsample of children with DB, paternal MD predicted criminality, consequences of antisocial behavior, truancy, poor school performance, and cumulative risk, while maternal MD predicted peer problems (mean OR = 1.94; range = 1.30-2.40; ps \< .05).

Conclusion
This study provides novel evidence that parental MD puts 9-year-olds with DB at risk for negative outcomes in adolescence. Additionally, paternal MD is a better predictor than maternal MD, regardless of child DB at age 9, suggesting that fathers should be given increased attention in future research. Treatment-as-usual of children with DB could be augmented with additional screening and, if necessary, treatment of mental health problems in their parents.

}, isbn = {0890-8567}, url = {https://doi.org/10.1016/j.jaac.2018.10.017}, author = {Roetman, Peter Josse and Lundstr{\"o}m, Sebastian and Finkenauer, Catrin and Vermeiren, Robert Rafa{\"e}l Joseph Marie and Lichtenstein, Paul and Colins, Olivier Frederiek} } @article {290, title = {The Complex Role of Parental Separation in the Association between Family Conflict and Child Problem Behavior}, journal = {Journal of Clinical Child \& Adolescent Psychology}, year = {2019}, pages = {1-15}, abstract = {

Parental separation is a major adverse childhood experience. Parental separation is generally preceded by conflict, which is itself a risk factor for child problem behavior. Whether parental separation independent of conflict has negative effects on child problem behavior is unclear. This study was embedded in Generation R, a population-based cohort followed from fetal life until age 9\ years. Information on family conflict was obtained from 5,808 mothers and fathers. The 4-way decomposition method was used to apportion the effects of prenatal family conflict and parental separation on child problem behavior into 4 nonoverlapping components. Structural equation modeling was used to test bidirectional effects of child problem behavior and family conflict over time. Family conflict from pregnancy onward and parental separation each strongly predicted child problem behavior up to preadolescence according to maternal and paternal ratings. Using the 4-way decomposition method, we found evidence for a strong direct effect of prenatal family conflict on child problem behavior, for reference interaction, and for mediated interaction. The evidence for interaction implies that prenatal family conflict increased the children\’s vulnerability to the harmful effect of parental separation. There was no evidence of a pure indirect effect of parental separation on child problem behavior. Overall, results indicated that if parental separation occurs in families with low levels of conflict, parental separation does not predict more child problem behavior. Moreover, the bidirectional pattern suggested that child problem behavior influences the persistence of family conflict.

}, doi = {10.1080/15374416.2018.1520118}, url = {https://doi.org/10.1080/15374416.2018.1520118}, author = {Yllza Xerxa and Leslie A. Rescorla and Fadila Serdarevic and Marinus H. Van IJzendorn and Vincent W. Jaddoe and Frank C. Verhulst and Maartje P.C.M. Luijk and Henning Tiemeier} } @article {324, title = {Data integration methods for phenotype harmonization in multi-cohort genome-wide association studies with behavioral outcomes}, journal = {Frontiers in Genetics}, volume = {10}, year = {2019}, pages = {1227}, abstract = {

Parallel meta-analysis is a popular approach for increasing the power to detect genetic effects in genome-wide association studies across multiple cohorts. Consortia studying the genetics of behavioral phenotypes are oftentimes faced with systematic differences in phenotype measurement across cohorts, introducing heterogeneity into the meta-analysis and reducing statistical power. This study investigated integrative data analysis (IDA) as an approach for jointly modeling the phenotype across multiple datasets. We put forth a bi-factor integration model (BFIM) that provides a single common phenotype score and accounts for sources of study-specific variability in the phenotype. In order to capitalize on this modeling strategy, a phenotype reference panel was utilized as a supplemental sample with complete data on all behavioral measures. A simulation study showed that a mega-analysis of genetic variant effects in a BFIM were more powerful than meta-analysis of genetic effects on a cohort-specific sum score of items. Saving the factor scores from the BFIM and using those as the outcome in meta-analysis was also more powerful than the sum score in most simulation conditions, but a small degree of bias was introduced by this approach. The reference panel was necessary to realize these power gains. An empirical demonstration used the BFIM to harmonize aggression scores in 9-year old children across the Netherlands Twin Register and the Child and Adolescent Twin Study in Sweden, providing a template for application of the BFIM to a range of different phenotypes. A supplemental data collection in the Netherlands Twin Register served as a reference panel for phenotype modeling across both cohorts. Our results indicate that model-based harmonization for the study of complex traits is a useful step within genetic consortia.

}, keywords = {consortia, data integration, genome-wide association studies, latent variable modeling, phenotype harmonization}, doi = {10.3389/fgene.2019.01227}, author = {Luningham, Justin M and McArtor, Daniel B and Hendriks, Anne M and van Beijsterveldt, Catharina E M and Lichtenstein, Paul and Lundstr{\"o}m, Sebastian and Larsson, Henrik and Bartels, Meike and Boomsma, Dorret I and Lubke, Gitta H} } @article {327, title = {DNA methylation signatures of breastfeeding in buccal cells collected in mid-childhood}, journal = {Nutrients}, volume = {11}, year = {2019}, pages = {2804}, abstract = {

Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized (\&$\#$39;never\&$\#$39; vs. \&$\#$39;ever\&$\#$39;). In the total sample, no robustly associated epigenome-wide significant CpGs were identified ($\alpha$ = 6.34 $\times$ 10-8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.

}, keywords = {ALSPAC., breastfeeding, DNA methylation, EPIC, EWAS, NTR, twins}, doi = {10.3390/nu11112804}, author = {Odintsova, Veronika V and Hagenbeek, Fiona A and Suderman, Matthew and Caramaschi, Doretta and van Beijsterveldt, Catharina E M and Kallsen, Noah A and Ehli, Erik A and Davies, Gareth E and Sukhikh, Gennady T and Fanos, Vassilios and Relton, Caroline and Bartels, Meike and Boomsma, Dorret I and van Dongen, Jenny} } @article {320, title = {Epigenome-wide association study of attention-deficit/hyperactivity disorder symptoms in adults}, journal = {Biological Psychiatry}, volume = {86}, year = {2019}, pages = {599{\textendash}607}, abstract = {

BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts.

METHODS: An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed.

RESULTS: One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92\% were associated with methylation quantitative trait loci, and 68\% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia.

CONCLUSIONS: Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.

}, keywords = {ADHD, CAARS, DNA methylation, Epigenetic, EWAS, Meta-analysis}, doi = {10.1016/j.biopsych.2019.02.016}, author = {van Dongen, Jenny and Zilh{\~a}o, Nuno R and Sugden, Karen and BIOS Consortium and Hannon, Eilis J and Mill, Jonathan and Caspi, Avshalom and Agnew-Blais, Jessica and Arseneault, Louise and Corcoran, David L and Moffitt, Terrie E and Poulton, Richie and Franke, Barbara and Boomsma, Dorret I} } @article {329, title = {Genetic and environmental influences on different forms of bullying perpetration, bullying victimization, and their co-occurrence}, journal = {Behavior Genetics}, volume = {49}, year = {2019}, pages = {432{\textendash}443}, abstract = {

Bullying comes in different forms, yet most previous genetically-sensitive studies have not distinguished between them. Given the serious consequences and the high prevalence of bullying, it is remarkable that the aetiology of bullying and its different forms has been under-researched. We present the first study to investigate the genetic architecture of bullying perpetration, bullying victimization, and their co-occurrence for verbal, physical and relational bullying. Primary-school teachers rated 8215 twin children on bullying perpetration and bullying victimization. For each form of bullying, we investigated, through genetic structural equation modelling, the genetic and environmental influences on being a bully, a victim or both. 34\% of the children were involved as bully, victim, or both. The correlation between being a bully and being a victim varied from 0.59 (relational) to 0.85 (physical). Heritability was \  70\% for perpetration and \  65\% for victimization, similar in girls and boys, yet both were somewhat lower for the relational form. Shared environmental influences were modest and more pronounced among girls. The correlation between being a bully and being a victim was explained mostly by genetic factors for verbal (\  71\%) and especially physical (\  77\%) and mostly by environmental factors for relational perpetration and victimization (\  60\%). Genes play a large role in explaining which children are at high risk of being a victim, bully, or both. For victimization this suggests an evocative gene-environment correlation: some children are at risk of being exposed to bullying, partly due to genetically influenced traits. So, genetic influences make some children more vulnerable to become a bully, victim or both.

}, keywords = {Bully-victims, Bullying, heritability, School, twins, Victimization}, doi = {10.1007/s10519-019-09968-5}, author = {Veldkamp, Sabine A M and Boomsma, Dorret I and de Zeeuw, Eveline L and van Beijsterveldt, Catharina E M and Bartels, Meike and Dolan, Conor V and van Bergen, Elsje} } @article {328, title = {Genomics of human aggression}, journal = {Psychiatric Genetics}, volume = {29}, year = {2019}, pages = {170{\textendash}190}, abstract = {

There are substantial differences, or variation, between humans in aggression, with its molecular genetic basis mostly unknown. This review summarizes knowledge on the genetic contribution to variation in aggression with the following three foci: (1) a comprehensive overview of reviews on the genetics of human aggression, (2) a systematic review of genome-wide association studies (GWASs), and (3) an automated tool for the selection of literature based on supervised machine learning. The phenotype definition \‘aggression\’ (or \‘aggressive behaviour\’, or \‘aggression-related traits\’) included anger, antisocial behaviour, conduct disorder, and oppositional defiant disorder. The literature search was performed in multiple databases, manually and using a novel automated selection tool, resulting in 18 reviews and 17 GWASs of aggression. Heritability estimates of aggression in children and adults are around 50\%, with relatively small fluctuations around this estimate. In 17 GWASs, 817 variants were reported as suggestive (P \≤ 1.0E\−05), including 10 significant associations (P \≤ 5.0E\−08). Nominal associations (P \≤ 1E\−05) were found in gene-based tests for genes involved in immune, endocrine, and nervous systems. Associations were not replicated across GWASs. A complete list of variants and their position in genes and chromosomes are available online. The automated literature search tool produced literature not found by regular search strategies. Aggression in humans is heritable, but its genetic basis remains to be uncovered. No sufficiently large GWASs have been carried out yet. With increases in sample size, we expect aggression to behave like other complex human traits for which GWAS has been successful.

}, doi = {10.1097/YPG.0000000000000239}, author = {Odintsova, Veronika V and Roetman, Peter J and Ip, Hill F and Pool, Ren{\'e} and Van der Laan, Camiel M and Tona, Klodiana-Daphne and Vermeiren, Robert R J M and Boomsma, Dorret I} } @article {287, title = {Interaction of schizophrenia polygenic risk and cortisol level on pre-adolescent brain structure}, journal = {Psychoneuroendocrinology}, volume = {101}, year = {2019}, pages = {295 - 303}, abstract = {

The etiology of schizophrenia is multi-factorial with early neurodevelopmental antecedents, likely to result from a complex interaction of genetic and environmental risk. However, few studies have examined how schizophrenia polygenic risk scores (PRS) are moderated by environmental factors in shaping neurodevelopmental brain structure, prior to the onset of psychotic symptoms. Here, we examined whether hair cortisol, a quantitative metric of chronic stress, moderated the association between genetic risk for schizophrenia and pre-adolescent brain structure. This study was embedded within the Generation R Study, involving pre-adolescents of European ancestry assessed regarding schizophrenia PRS, hair cortisol, and brain imaging (n\ =\ 498 structural; n\ =\ 526 diffusion tensor imaging). Linear regression was performed to determine the association between schizophrenia PRS, hair cortisol level, and brain imaging outcomes. Although no single measure exceeded the multiple testing threshold, nominally significant interactions were observed for total ventricle volume (Pinteraction = 0.02) and global white matter microstructure (Pinteraction = 0.01) \– two of the most well replicated brain structural findings in schizophrenia. These findings provide suggestive evidence for the joint effects of schizophrenia liability and cortisol levels on brain correlates in the pediatric general population. Given the widely replicated finding of ventricular enlargement and lower white matter integrity among schizophrenia patients, our findings generate novel hypotheses for future research on gene-environment interactions affecting the neurodevelopmental pathophysiology of schizophrenia.

}, keywords = {Diffusion tensor imaging, Gene-environment, Genetic, Neuroimaging, Psychosis, Stress}, issn = {0306-4530}, doi = {https://doi.org/10.1016/j.psyneuen.2018.12.231}, url = {http://www.sciencedirect.com/science/article/pii/S0306453018308862}, author = {Koen Bolhuis and Henning Tiemeier and Philip R. Jansen and Ryan L. Muetzel and Alexander Neumann and Manon H.J. Hillegers and Erica T.L. van den Akker and Elisabeth F.C. van Rossum and Vincent W.V. Jaddoe and Meike W. Vernooij and Tonya White and Steven A. Kushner} } @article {321, title = {Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight}, journal = {Nature Communications}, volume = {10}, year = {2019}, pages = {1893}, abstract = {

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10\% increase in methylation (PBonferroni \< 1.06 x 10-7). In additional analyses in 7,278 participants, \<1.3\% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/91

}, doi = {10.1038/s41467-019-09671-3}, author = {K{\"u}pers, Leanne K and Monnereau, Claire and Sharp, Gemma C and Yousefi, Paul and Salas, Lucas A and Ghantous, Akram and Page, Christian M and Reese, Sarah E and Wilcox, Allen J and Czamara, Darina and Starling, Anne P and Novoloaca, Alexei and Lent, Samantha and Roy, Ritu and Hoyo, Cathrine and Breton, Carrie V and Allard, Catherine and Just, Allan C and Bakulski, Kelly M and Holloway, John W and Everson, Todd M and Xu, Cheng-Jian and Huang, Rae-Chi and van der Plaat, Diana A and Wielscher, Matthias and Merid, Simon Kebede and Ullemar, Vilhelmina and Rezwan, Faisal I and Lahti, Jari and van Dongen, Jenny and Langie, Sabine A S and Richardson, Tom G and Magnus, Maria C and Nohr, Ellen A and Xu, Zongli and Duijts, Liesbeth and Zhao, Shanshan and Zhang, Weiming and Plusquin, Michelle and DeMeo, Dawn L and Solomon, Olivia and Heimovaara, Joosje H and Jima, Dereje D and Gao, Lu and Bustamante, Mariona and Perron, Patrice and Wright, Robert O and Hertz-Picciotto, Irva and Zhang, Hongmei and Karagas, Margaret R and Gehring, Ulrike and Marsit, Carmen J and Beilin, Lawrence J and Vonk, Judith M and Jarvelin, Marjo-Riitta and Bergstr{\"o}m, Anna and {\"O}rtqvist, Anne K and Ewart, Susan and Villa, Pia M and Moore, Sophie E and Willemsen, Gonneke and Standaert, Arnout R L and H\aaberg, Siri E and S{\o}rensen, Thorkild I A and Taylor, Jack A and R{\"a}ikk{\"o}nen, Katri and Yang, Ivana V and Kechris, Katerina and Nawrot, Tim S and Silver, Matt J and Gong, Yun Yun and Richiardi, Lorenzo and Kogevinas, Manolis and Litonjua, Augusto A and Eskenazi, Brenda and Huen, Karen and Mbarek, Hamdi and Maguire, Rachel L and Dwyer, Terence and Vrijheid, Martine and Bouchard, Luigi and Baccarelli, Andrea A and Croen, Lisa A and Karmaus, Wilfried and Anderson, Denise and de Vries, Maaike and Sebert, Sylvain and Kere, Juha and Karlsson, Robert and Arshad, Syed Hasan and H{\"a}m{\"a}l{\"a}inen, Esa and Routledge, Michael N and Boomsma, Dorret I and Feinberg, Andrew P and Newschaffer, Craig J and Govarts, Eva and Moisse, Matthieu and Fallin, M Daniele and Mel{\'e}n, Erik and Prentice, Andrew M and Kajantie, Eero and Almqvist, Catarina and Oken, Emily and Dabelea, Dana and Boezen, H Marike and Melton, Phillip E and Wright, Rosalind J and Koppelman, Gerard H and Trevisi, Letizia and Hivert, Marie-France and Sunyer, Jordi and Munthe-Kaas, Monica C and Murphy, Susan K and Corpeleijn, Eva and Wiemels, Joseph and Holland, Nina and Herceg, Zdenko and Binder, Elisabeth B and Davey Smith, George and Jaddoe, Vincent W V and Lie, Rolv T and Nystad, Wenche and London, Stephanie J and Lawlor, Debbie A and Relton, Caroline L and Snieder, Harold and Felix, Janine F} } @article {323, title = {The Netherlands Twin Register: Longitudinal research based on twin and twin-family designs}, journal = {Twin Research and Human Genetics}, volume = {22}, year = {2019}, pages = {623{\textendash}636}, abstract = {

The Netherlands Twin Register (NTR) is a national register in which twins, multiples and their parents, siblings, spouses and other family members participate. Here we describe the NTR resources that were created from more than 30 years of data collections; the development and maintenance of the newly developed database systems, and the possibilities these resources create for future research. Since the early 1980s, the NTR has enrolled around 120,000 twins and a roughly equal number of their relatives. The majority of twin families have participated in survey studies, and subsamples took part in biomaterial collection (e.g., DNA) and dedicated projects, for example, for neuropsychological, biomarker and behavioral traits. The recruitment into the NTR is all inclusive without any restrictions on enrollment. These resources - the longitudinal phenotyping, the extended pedigree structures and the multigeneration genotyping - allow for future twin-family research that will contribute to gene discovery, causality modeling, and studies of genetic and cultural inheritance.

}, keywords = {biobank, endophenotyping, longitudinal phenotyping, multigeneration pedigree, twins, zygosity}, doi = {10.1017/thg.2019.93}, author = {Ligthart, Lannie and van Beijsterveldt, Catharina E M and Kevenaar, Sofieke T and de Zeeuw, Eveline and van Bergen, Elsje and Bruins, Susanne and Pool, Ren{\'e} and Helmer, Quinta and van Dongen, Jenny and Hottenga, Jouke-Jan and Van{\textquoteright}t Ent, Dennis and Dolan, Conor V and Davies, Gareth E and Ehli, Erik A and Bartels, Meike and Willemsen, Gonneke and de Geus, Eco J C and Boomsma, Dorret I} } @article {318, title = {Testing bidirectional associations between childhood aggression and BMI: Results from three cohorts}, journal = {Obesity (Silver Spring)}, volume = {27}, year = {2019}, pages = {822{\textendash}829}, abstract = {

OBJECTIVE: This study examined the prospective, potentially bidirectional association of aggressive behavior with BMI and body composition across childhood in three population-based cohorts.

METHODS: Repeated measures of aggression and BMI were available from the Generation R Study between ages 6 and 10 years (N = 3,974), the Netherlands Twin Register (NTR) between ages 7 and 10 years (N = 10,328), and the Swedish Twin Study of Child and Adolescent Development (TCHAD) between ages 9 and 14 years (N = 1,462). In all samples, aggression was assessed with the Child Behavior Checklist. Fat mass and fat-free mass were available in the Generation R Study. Associations were examined with cross-lagged modeling.

RESULTS: Aggressive behavior at baseline was associated with higher BMI at follow-up in the Generation R Study ($\beta$ = 0.02, 95\% CI: 0.00 to 0.04), in NTR ($\beta$ = 0.04, 95\% CI: 0.02 to 0.06), and in TCHAD ($\beta$ = 0.03, 95\% CI: -0.02 to 0.07). Aggressive behavior was prospectively associated with higher fat mass ($\beta$ = 0.03, 95\% CI: 0.01 to 0.05) but not fat-free mass. There was no evidence that BMI or body composition preceded aggressive behavior.

CONCLUSIONS: More aggressive behavior was prospectively associated with higher BMI and fat mass. This suggests that aggression contributes to the obesity problem, and future research should study whether these behavioral pathways to childhood obesity are modifiable.

}, doi = {10.1002/oby.22419}, author = {Derks, Ivonne P M and Bolhuis, Koen and Yalcin, Zeynep and Gaillard, Romy and Hillegers, Manon H J and Larsson, Henrik and Lundstr{\"o}m, Sebastian and Lichtenstein, Paul and van Beijsterveldt, Catharina E M and Bartels, Meike and Boomsma, Dorret I and Tiemeier, Henning and Jansen, Pauline W} } @article {331, title = {Tracking of voluntary exercise behaviour over the lifespan}, journal = {International Journal of Behavioral Nutrition and Physical Activity}, volume = {16}, year = {2019}, pages = {17}, abstract = {

BACKGROUND: The aim of many physical activity interventions is to develop life-long habits of regular exercise and sports activities in leisure time. Previous studies that assessed tracking (i.e. the stability of a trait over the lifespan) of leisure time exercise behaviour across various parts of the life span have treated it as a uniform construct by summing all types of leisure time exercise activities into a single summary score for the total volume of exercise. This study provides new insight by additionally determining tracking across leisure time exercise activities in six different domains: (1) team-based versus solitary activities, (2) competitive versus non-competitive activities, and (3) externally paced versus internally paced activities. We also assessed which of the domains of exercise activities best predicted total volume of exercise at follow-up.

METHODS: A large dataset (N = 43,889) from the Netherlands Twin Register (NTR) was used to analyse the tracking of exercise behaviour over time. Using this dataset, we were able to examine tracking as a function of baseline age (8 to 80 years) and tracking duration (2 to 22-year follow-up), taking into account sex differences, using generalized estimating equations.

RESULTS: Two-year tracking coefficients are moderate to high for total volume of exercise across ages at baseline, ranging from .38 to .77 with a median of .57. Tracking coefficients tend to decrease as the distance to follow-up increases, down to a median of .38 for the 22-year tracking coefficients. The patterns of tracking were largely domain-independent and were largely similar for solitary, competitive, non-competitive, externally and internally paced activities. With the exception of team-based activities, tracking was seen to increase as a function of baseline age. Cross-domain tracking did not favour any specific domain of exercise activity as the best predictor for total volume of exercise behaviour and this was true at all baseline ages.

CONCLUSION: We conclude that exercise behaviour is moderately to highly stable across the life span. In particular in adulthood, where the tracking of exercise mimics that of a classical behavioural trait like personality. This stability reinforces existing evidence that exercise habits are hard to change, but at the same time suggests that successful intervention leading to the adoption of exercise habits will tend to last.

}, keywords = {Behavioural trends, Competitive exercise, Leisure time physical activity, Lifespan, Longitudinal stability, Team exercise}, doi = {10.1186/s12966-019-0779-4}, author = {van der Zee, Matthijs D and van der Mee, Denise and Bartels, Meike and de Geus, Eco J C} } @article {236, title = {Adult aggressive behavior in humans and biomarkers: a focus on lipids and methylation}, journal = {Journal of Pediatric and Neonatal Individualized Medicine (JPNIM)}, volume = {7}, year = {2018}, month = {04/2018}, abstract = {

Aggression shows large variation between individuals, with about 50\% explained by genetic factors. Biomarkers related to aggression have been reported for lipid metabolism and for epigenetic marks. Methylation and blood lipid levels are not independent and differential methylation can be a consequence of variation in blood lipid levels. We hypothesized that the methylation level of such loci in blood can inform us if aggression is associated with long-term exposure to lipid levels. If this is the case, we expect to find that loci where methylation levels are influenced by lipid levels to show differential methylation in aggressive individuals. Such loci might complement classic lipid level measures as a biomarker for lipid-related disturbances in aggression. As a first step, we examined the association of lipid levels and related biomarkers with aggression in a large adult population cohort (N = 5,588) and in 31 monozygotic (MZ) twin pairs who were discordant for aggression, as well as 12 extremely discordant MZ pairs. Biomarkers were not significantly associated with aggression in the population cohort. In the discordant MZ pairs we identified significant within-pair differences for glucose and marginally significant differences for lipids and cytokines, with the more aggressive twin showing lower levels of glucose and low density lipoprotein cholesterol and higher levels of fibrinogen, C-reactive protein and interleukin-6. The analysis of epigenetic data in the MZ pairs discordant for aggression did not show enrichment for lipid cytosine guanine dinucleotides (CpGs) and we observed no enrichment of lipid CpGs in an epigenome-wide association study of aggression in the population cohort. These results did not support the hypothesis that lipid CpGs show differential methylation in adult aggression. A next step will be to examine the role of biomarkers in aggression across the lifespan, including childhood, and to explore a more holistic biomarker approach, such as offered by metabolomics.

PDF Available here

}, keywords = {adult aggression, biomarkers, discordant twin pairs, epigenetics, lipids}, doi = {10.7363/070204}, url = {http://www.jpnim.com/index.php/jpnim/article/view/070204}, author = {Fiona Hagenbeek and Jenny van Dongen and Kluft, Cornelis and Thomas Hankemeier and Lannie Ligthart and Gonneke Willemsen and de Geus, Eco J.C. and Vink, Jacqueline M. and Meike Bartels and Dorret I. Boomsma} } @article {274, title = {Aggressive behaviour in childhood and adolescence: the role of smoking during pregnancy, evidence from four twin cohorts in the EU-ACTION consortium}, journal = {Psychological Medicine}, year = {2018}, pages = {1{\textendash}9}, abstract = {

BACKGROUND:

Maternal smoking during pregnancy (MSDP) has been linked to offspring\&$\#$39;s externalizing problems. It has been argued that socio-demographic factors (e.g. maternal age and education), co-occurring environmental risk factors, or pleiotropic genetic effects may account for the association between MSDP and later outcomes. This study provides a comprehensive investigation of the association between MSDP and a single harmonized component of externalizing: aggressive behaviour, measured throughout childhood and adolescence.

METHODS:

Data came from four prospective twin cohorts - Twins Early Development Study, Netherlands Twin Register, Childhood and Adolescent Twin Study of Sweden, and FinnTwin12 study - who collaborate in the EU-ACTION consortium. Data from 30 708 unrelated individuals were analysed. Based on item level data, a harmonized measure of aggression was created at ages 9-10; 12; 14-15 and 16-18.

RESULTS:

MSDP predicted aggression in childhood and adolescence. A meta-analysis across the four samples found the independent effect of MSDP to be 0.4\% (r = 0.066), this remained consistent when analyses were performed separately by sex. All other perinatal factors combined explained 1.1\% of the variance in aggression across all ages and samples (r = 0.112). Paternal smoking and aggressive parenting strategies did not account for the MSDP-aggression association, consistent with the hypothesis of a small direct link between MSDP and aggression.

CONCLUSIONS:

Perinatal factors, including MSDP, account for a small portion of the variance in aggression in childhood and adolescence. Later experiences may play a greater role in shaping adolescents\&$\#$39; aggressive behaviour.

}, doi = {10.1017/S0033291718001344}, author = {Malanchini, Margherita and Emily Smith-Woolley and Ayorech, Ziada and Kaili Rimfeld and Eva Krapohl and Vuoksimaa, Eero and Korhonen, Tellervo and Meike Bartels and van Beijsterveldt, Toos C.E.M. and Richard J. Rose and et al.} } @article {249, title = {Characterizing the Relation Between Expression QTLs and Complex Traits: Exploring the Role of Tissue Specificity}, journal = {Behavior Genetics}, volume = {48}, year = {2018}, month = {Sep}, pages = {374{\textendash}385}, abstract = {

Measurement of gene expression levels and detection of eQTLs (expression quantitative trait loci) are difficult in tissues with limited sample availability, such as the brain. However, eQTL overlap between tissues might be high, which would allow for inference of eQTL functioning in the brain via eQTLs detected in readily accessible tissues, e.g. whole blood. Applying Stratified Linkage Disequilibrium Score Regression (SLDSR), we quantified the enrichment in polygenic signal of blood and brain eQTLs in genome-wide association studies (GWAS) of 11 complex traits. We looked at eQTLs discovered in 44 tissues by the Genotype-Tissue Expression (GTEx) consortium and two other large representative studies, and found no tissue-specific eQTL effects. Next, we integrated the GTEx eQTLs with regions associated with tissue-specific histone modifiers, and interrogated their effect on rheumatoid arthritis and schizophrenia. We observed substantially enriched effects of eQTLs located inside regions bearing modification H3K4me1 on schizophrenia, but not rheumatoid arthritis, and not tissue-specific. Finally, we extracted eQTLs associated with tissue-specific differentially expressed genes and determined their effects on rheumatoid arthritis and schizophrenia, these analysis revealed limited enrichment of eQTLs associated with gene specifically expressed in specific tissues. Our results pointed to strong enrichment of eQTLs in their effect on complex traits, without evidence for tissue-specific effects. Lack of tissue-specificity can be either due to a lack of statistical power or due to the true absence of tissue-specific effects. We conclude that eQTLs are strongly enriched in GWAS signal and that the enrichment is not specific to the eQTL discovery tissue. Until sample sizes for eQTL discovery grow sufficiently large, working with relatively accessible tissues as proxy for eQTL discovery is sensible and restricting lookups for GWAS hits to a specific tissue for which limited samples are available might not be advisable.

}, issn = {1573-3297}, doi = {10.1007/s10519-018-9914-2}, url = {https://doi.org/10.1007/s10519-018-9914-2}, author = {Ip, Hill F. and Jansen, Rick and Abdellaoui, Abdel and Meike Bartels and UK Brain Expression Consortium and Ryten, Mina and Hardy, John and Weale, Michael E. and Ramasamy, Adaikalavan and Forabosco, Paola and Matarin, Mar and Vandrovcova, Jana and Botia, Juan A. and D{\textquoteright}Sa, Karishma and Guelfi, Sebastian and Smith, Colin and Walker, Robert and Reynolds, Regina H. and Zhang, David and Trabzuni, Daniah and Dorret I. Boomsma and Michel G. Nivard} } @article {230, title = {Childhood aggression and the co-occurrence of behavioural and emotional problems: results across ages 3{\textendash}16~years from multiple raters in six cohorts in the EU-ACTION project}, journal = {European Child {\&} Adolescent Psychiatry}, year = {2018}, month = {May}, abstract = {

Childhood aggression and its resulting consequences inflict a huge burden on affected children, their relatives, teachers, peers and society as a whole. Aggression during childhood rarely occurs in isolation and is correlated with other symptoms of childhood psychopathology. In this paper, we aim to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychopathology. We focus on the co-occurrence of aggression and other childhood behavioural and emotional problems, including other externalising problems, attention problems and anxiety\–depression. The data were brought together within the EU-ACTION (Aggression in Children: unravelling gene-environment interplay to inform Treatment and InterventiON strategies) project. We analysed the co-occurrence of aggression and other childhood behavioural and emotional problems as a function of the child\&$\#$39;s age (ages 3 through 16\ years), gender, the person rating the behaviour (father, mother or self) and assessment instrument. The data came from six large population-based European cohort studies from the Netherlands (2x), the UK, Finland and Sweden (2x). Multiple assessment instruments, including the Child Behaviour Checklist (CBCL), the Strengths and Difficulties Questionnaire (SDQ) and Multidimensional Peer Nomination Inventory (MPNI), were used. There was a good representation of boys and girls in each age category, with data for 30,523 3- to 4-year-olds (49.5{\%} boys), 20,958 5- to 6-year-olds (49.6{\%} boys), 18,291 7- to 8-year-olds (49.0{\%} boys), 27,218 9- to 10-year-olds (49.4{\%} boys), 18,543 12- to 13-year-olds (48.9{\%} boys) and 10,088 15- to 16-year-olds (46.6{\%} boys). We replicated the well-established gender differences in average aggression scores at most ages for parental ratings. The gender differences decreased with age and were not present for self-reports. Aggression co-occurred with the majority of other behavioural and social problems, from both externalising and internalising domains. At each age, the co-occurrence was particularly prevalent for aggression and oppositional and ADHD-related problems, with correlations of around 0.5 in general. Aggression also showed substantial associations with anxiety\–depression and other internalizing symptoms (correlations around 0.4). Co-occurrence for self-reported problems was somewhat higher than for parental reports, but we found neither rater differences, nor differences across assessment instruments in co-occurrence patterns. There were large similarities in co-occurrence patterns across the different European countries. Finally, co-occurrence was generally stable across age and sex, and if any change was observed, it indicated stronger correlations when children grew older. We present an online tool to visualise these associations as a function of rater, gender, instrument and cohort. In addition, we present a description of the full EU-ACTION projects, its first results and the future perspectives.

Related interactive tool here.

}, issn = {1435-165X}, doi = {10.1007/s00787-018-1169-1}, url = {https://doi.org/10.1007/s00787-018-1169-1}, author = {Meike Bartels and Anne Hendriks and Matteo Mauri and Eva Krapohl and Alyce Whipp and Koen Bolhuis and Conde, Lucia Colodro and Luningham, Justin and Fung Ip, Hill and Fiona Hagenbeek and Roetman, Peter and Gatej, Raluca and Lamers, Audri and Michel G. Nivard and Jenny van Dongen and Lu, Yi and Christel Middeldorp and van Beijsterveldt, Toos and Vermeiren, Robert and Thomas Hankemeier and Kluft, Cees and Medland, Sarah and Lundstr{\"o}m, Sebastian and Richard J. Rose and Pulkkinen, Lea and Vuoksimaa, Eero and Korhonen, Tellervo and Martin, Nicholas G. and Gitta Lubke and Catrin Finkenauer and Vassilios Fanos and Henning Tiemeier and Lichtenstein, Paul and Robert Plomin and Kaprio, Jaakko and Dorret I. Boomsma} } @article {259, title = {Differences in exam performance between pupils attending selective and non-selective schools mirror the genetic differences between them}, volume = {3}, year = {2018}, month = {2018/03/23}, pages = {3}, abstract = {

On average, students attending selective schools outperform their non-selective counterparts in national exams. These differences are often attributed to value added by the school, as well as factors schools use to select pupils, including ability, achievement and, in cases where schools charge tuition fees or are located in affluent areas, socioeconomic status. However, the possible role of DNA differences between students of different schools types has not yet been considered. We used a UK-representative sample of 4814 genotyped students to investigate exam performance at age 16 and genetic differences between students in three school types: state-funded, non-selective schools (\‘non-selective\’), state-funded, selective schools (\‘grammar\’) and private schools, which are selective (\‘private\’). We created a genome-wide polygenic score (GPS) derived from a genome-wide association study of years of education (EduYears). We found substantial mean genetic differences between students of different school types: students in non-selective schools had lower EduYears GPS compared to those in grammar (d\ =\ 0.41) and private schools (d\ =\ 0.37). Three times as many students in the top EduYears GPS decile went to a selective school compared to the bottom decile. These results were mirrored in the exam differences between school types. However, once we controlled for factors involved in pupil selection, there were no significant genetic differences between school types, and the variance in exam scores at age 16 explained by school type dropped from 7\% to \<1\%. These results show that genetic and exam differences between school types are primarily due to the heritable characteristics involved in pupil admission.

}, isbn = {2056-7936}, url = {https://doi.org/10.1038/s41539-018-0019-8}, author = {Emily Smith-Woolley and Pingault, Jean-Baptiste and Saskia Selzam and Kaili Rimfeld and Eva Krapohl and Sophie von Stumm and Asbury, Kathryn and Philip S. Dale and Young, Toby and Allen, Rebecca and Yulia Kovas and Robert Plomin} } @article {261, title = {DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis}, journal = {Blood}, year = {2018}, abstract = {

Elevated epigenetic age is associated with an altered hemostatic factor profile and lower clotting time (aPTT).DNA methylation age is associated with mRNA levels of fibrinogen in multiple tissues. Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95\% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95\% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

}, issn = {0006-4971}, doi = {10.1182/blood-2018-02-831347}, url = {http://www.bloodjournal.org/content/early/2018/07/24/blood-2018-02-831347}, author = {Ward-Caviness, Cavin K. and Huffman, Jennifer E. and Evertt, Karl and Germain, Marine and van Dongen, Jenny and Hill, W. David and Jhun, Min A. and Brody, Jennifer A. and Ghanbari, Mohsen and Du, Lei and Roetker, Nicholas S. and de Vries, Paul S. and Waldenberger, Melanie and Gieger, Christian and Wolf, Petra and Prokisch, Holger and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J. and Levy, Daniel and Liu, Chunyu and Truong, Vinh and Wells, Philip S. and Tr{\'e}gou{\"e}t, David-Alexandre and Tang, Weihong and Morrison, Alanna C. and Boerwinkle, Eric and Wiggins, Kerri L. and McKnight, Barbara and Guo, Xiuqing and Psaty, Bruce M. and Sotoodenia, Nona and Dorret I. Boomsma and Gonneke Willemsen and Lannie Ligthart and Deary, Ian J. and Zhao, Wei and Ware, Erin B. and Kardia, Sharon L.R. and Joyce B.J. Van Meurs and Uitterlinden, Andre G. and Franco, Oscar H. and Eriksson, Per and Franco-Cereceda, Anders and Pankow, James S. and Johnson, Andrew D. and Gagnon, France and Morange, Pierre-Emmanuel and de Geus, Eco J.C. and Starr, John M. and Smith, Jennifer A. and Dehghan, Abbas and Bj{\"o}rck, Hanna M. and Smith, Nicholas L. and Peters, Annette} } @article {227, title = {DNA methylation signatures of educational attainment}, volume = {3}, year = {2018}, month = {2018/03/23}, pages = {7}, abstract = {

Educational attainment is a key behavioural measure in studies of cognitive and physical health, and socioeconomic status. We measured DNA methylation at 410,746 CpGs (N\ =\ 4152) and identified 58 CpGs associated with educational attainment at loci characterized by pleiotropic functions shared with neuronal, immune and developmental processes. Associations overlapped with those for smoking behaviour, but remained after accounting for smoking at many CpGs: Effect sizes were on average 28\% smaller and genome-wide significant at 11 CpGs after adjusting for smoking and were 62\% smaller in never smokers. We examined sources and biological implications of education-related methylation differences, demonstrating correlations with maternal prenatal folate, smoking and air pollution signatures, and associations with gene expression in cis, dynamic methylation in foetal brain, and correlations between blood and brain. Our findings show that the methylome of lower-educated people resembles that of smokers beyond effects of their own smoking behaviour and shows traces of various other exposures.

}, isbn = {2056-7936}, url = {https://doi.org/10.1038/s41539-018-0020-2}, author = {Jenny van Dongen and Bonder, Marc Jan and Dekkers, Koen F. and Michel G. Nivard and van Iterson, Maarten and Gonneke Willemsen and Beekman, Marian and van der Spek, Ashley and Joyce B.J. Van Meurs and Franke, Lude and Bastiaan T. Heijmans and van Duijn, Cornelia M. and Slagboom, P. Eline and Dorret I. Boomsma} } @article {315, title = {Do parental psychiatric symptoms predict outcome in children with psychiatric disorders? A naturalistic clinical study}, journal = {Journal of the American Academy of Child \& Adolescent Psychiatry}, volume = {57}, year = {2018}, pages = {669{\textendash}677.e6}, abstract = {

OBJECTIVE: Parental psychiatric symptoms can negatively affect the outcome of children\&$\#$39;s psychopathology. Studies thus far have mainly shown a negative effect of maternal depression. This study examined the associations between a broad range of psychiatric symptoms in mothers and fathers and the child\&$\#$39;s outcome. METHOD: Internalizing and externalizing psychiatric symptoms were assessed in 742 mothers, 440 fathers, and their 811 children at the first evaluation in 3 child and adolescent psychiatric outpatient clinics and at follow-up (on average 1.7 years later). Predictions of child\&$\#$39;s symptoms scores were tested at follow-up by parental symptom scores at baseline, parental scores at follow-up, and offspring scores at baseline. RESULTS: Children whose mother or father scored above the (sub)clinical threshold for psychiatric symptoms at baseline had higher symptom scores at baseline and at follow-up. Offspring follow-up scores were most strongly predicted by offspring baseline scores, in addition to parental psychiatric symptoms at follow-up. Offspring symptom scores at follow-up generally were not predicted by parental scores at baseline. Maternal and paternal associations were of similar magnitude. CONCLUSION: Higher symptom scores at follow-up in children of parents with psychopathology were mainly explained by higher symptom scores at baseline. Continuing parent-offspring associations could be a result of reciprocal effects, ie, parental symptoms influencing offspring symptoms and offspring symptoms influencing parental symptoms. Nevertheless, the results show that these children are at risk for persisting symptoms, possibly indicating the need to treat maternal and paternal psychopathology.

}, keywords = {child psychopathology, longitudinal, parent-offspring associations, parental psychopathology}, doi = {10.1016/j.jaac.2018.05.017}, author = {Wesseldijk, Laura W and Dieleman, Gwen C and van Steensel, Francisca J A and Bleijenberg, Ellen J and Bartels, Meike and B{\"o}gels, Susan M and Middeldorp, Christel M} } @article {277, title = {During day and night: Childhood psychotic experiences and objective and subjective sleep problems}, journal = {Schizophrenia Research}, year = {2018}, abstract = {

Background
Psychotic experiences comprise auditory and visual perceptive phenomena, such as hearing or seeing things that are not there, in the absence of a psychotic disorder. Psychotic experiences commonly occur in the general pediatric population. Although the majority of psychotic experiences are transient, they are predictive of future psychotic and non-psychotic disorders. They have been associated with sleep problems, but studies with objective sleep measures are lacking. This study assessed whether psychotic experiences were associated with actigraphic sleep measures, symptoms of dyssomnia, nightmares, or other parasomnias.


Methods
This cross-sectional population-based study comprises 4149 children from the Generation R Study. At age 10 years, psychotic experiences including hallucinatory phenomena were assessed by self-report; dyssomnia and parasomnia symptoms were assessed by mother- and child-report. Additionally, at age 11 years, objective sleep parameters were measured using a tri-axial wrist accelerometer in N = 814 children, who wore the accelerometer for five consecutive school days.

Results
Psychotic experiences were not associated with objective sleep duration, sleep efficiency, arousal, or social jetlag. However, psychotic experiences were associated with self-reported dyssomnia (B = 2.45, 95\%CI: 2.13\–2.77, p \< 0.001) and mother-reported parasomnia, specifically nightmares (ORadjusted = 3.59, 95\%CI 2.66\–4.83, p \< 0.001). Similar results were found when analyses were restricted to hallucinatory phenomena.

Conclusions
Childhood psychotic experiences were not associated with objective sleep measures. In contrast, psychotic experiences were associated with nightmares, which are a known risk indicator of psychopathology in pre-adolescence. More research is needed to shed light on the potential etiologic or diagnostic role of nightmares in the development of psychotic phenomena.

}, keywords = {Actigraphy, General population, Hallucinatory phenomena, Parasomnia, Psychosis, Social jetlag}, issn = {0920-9964}, doi = {https://doi.org/10.1016/j.schres.2018.12.002}, url = {http://www.sciencedirect.com/science/article/pii/S0920996418306911}, author = {M. Elisabeth Koopman-Verhoeff and Koen Bolhuis and Charlotte A.M. Cecil and Desana Kocevska and J.J. Hudziak and Manon H.J. Hillegers and Viara R. Mileva-Seitz and Irwin K. Reiss and Liesbeth Duijts and Frank Verhulst and Maartje P.C.M. Luijk and Henning Tiemeier} } @article {254, title = {Early adolescent aggression predicts antisocial personality disorder in young adults: a population-based study}, journal = {European Child {\&} Adolescent Psychiatry}, year = {2018}, month = {Jul}, abstract = {

Modestly prevalent in the general population ({\textasciitilde}{\th}inspace}4{\%}), but highly prevalent in prison populations (\>{\th}inspace}40{\%}), the diagnosis of antisocial personality disorder (ASPD) involves aggression as one of several possible criteria. Using multiple informants, we aimed to determine if general aggression, as well as direct and indirect subtypes, assessed in early adolescence (ages 12, 14) predict young adulthood ASPD in a population-based sample. Using data from a Finnish population-based longitudinal twin cohort study with psychiatric interviews available at age 22 (N{\th}inspace}={\th}inspace}1347), we obtained DSM-IV-based ASPD diagnoses. Aggression measures from ages 12 (parental and teacher ratings) and 14 (teacher, self, and co-twin ratings) were used to calculate odds ratios (OR) of ASPD from logistic regression models and the area under the curve (AUC) from receiver operating characteristic curve analysis. Analyses were adjusted for sex, age, and family structure. All informants\&$\#$39; aggression ratings were significant (p{\th}inspace}\<{\th}inspace}0.05) predictors of ASPD (OR range 1.3\–1.8; AUC range 0.65\–0.72). Correlations between informants ranged from 0.13 to 0.33. Models including two or more aggression ratings, particularly age 14 teacher and self ratings, more accurately predicted ASPD (AUC: 0.80; 95{\%} confidence interval 0.73\–0.87). Direct aggression rated by all informants significantly predicted ASPD (OR range 1.4\–1.9), whereas only self-rated indirect aggression was significantly associated with ASPD (OR{\th}inspace}={\th}inspace}1.4). Across different informants, general and direct aggression at ages 12 and 14 predicted ASPD in a population-based sample. Psychiatric, social, and parenting interventions for ASPD prevention should focus on children and adolescents with high aggression levels, with an aim to gather information from multiple informants.

}, issn = {1435-165X}, doi = {10.1007/s00787-018-1198-9}, url = {https://doi.org/10.1007/s00787-018-1198-9}, author = {Alyce Whipp and Korhonen, Tellervo and Raevuori, Anu and Heikkil{\"a}, Kauko and Pulkkinen, Lea and Richard J. Rose and Kaprio, Jaakko and Vuoksimaa, Eero} } @article {293, title = {Genetic and Environmental Influences on Self-Control: Assessing Self-Control with the ASEBA Self-Control Scale}, journal = {Behavior Genetics}, volume = {48}, year = {2018}, month = {Mar}, pages = {135{\textendash}146}, abstract = {

This study used a theoretically-derived set of items of the Achenbach System of Empirically Based Assessment to develop the Achenbach Self-Control Scale (ASCS) for 7\–16\ year olds. Using a large dataset of over 20,000 children, who are enrolled in the Netherlands Twin Register, we demonstrated the psychometric properties of the ASCS for parent-, self- and teacher-report by examining internal and criterion validity, and inter-rater and test\–retest reliability. We found associations between the ASCS and measures of well-being, educational achievement, and substance use. Next, we applied the classical twin design to estimate the genetic and environmental contributions to self-control. Genetic influences accounted for 64\–75{\%} of the variance in self-control based on parent- and teacher-report (age 7\–12), and for 47\–49{\%} of the variance in self-control based on self-report (age 12\–16), with the remaining variance accounted by non-shared environmental influences. In conclusion, we developed a validated and accessible self-control scale, and show that genetic influences explain a majority of the individual differences in self-control across youth aged 7\–16\ years.

}, issn = {1573-3297}, doi = {10.1007/s10519-018-9887-1}, url = {https://doi.org/10.1007/s10519-018-9887-1}, author = {Willems, Yayouk E. and Dolan, Conor V. and van Beijsterveldt, Catharina E. M. and de Zeeuw, Eveline L. and Boomsma, Dorret I. and Bartels, Meike and Finkenauer, Catrin} } @article {279, title = {The genetics of university success}, volume = {8}, year = {2018}, month = {2018/10/18}, pages = {14579}, abstract = {

University success, which includes enrolment in and achievement at university, as well as quality of the university, have all been linked to later earnings, health and wellbeing. However, little is known about the causes and correlates of differences in university-level outcomes. Capitalizing on both quantitative and molecular genetic data, we perform the first genetically sensitive investigation of university success with a UK-representative sample of 3,000 genotyped individuals and 3,000 twin pairs. Twin analyses indicate substantial additive genetic influence on university entrance exam achievement (57\%), university enrolment (51\%), university quality (57\%) and university achievement (46\%). We find that environmental effects tend to be non-shared, although the shared environment is substantial for university enrolment. Furthermore, using multivariate twin analysis, we show moderate to high genetic correlations between university success variables (0.27\–0.76). Analyses using DNA alone also support genetic influence on university success. Indeed, a genome-wide polygenic score, derived from a 2016 genome-wide association study of years of education, predicts up to 5\% of the variance in each university success variable. These findings suggest young adults select and modify their educational experiences in part based on their genetic propensities and highlight the potential for DNA-based predictions of real-world outcomes, which will continue to increase in predictive power.

}, isbn = {2045-2322}, url = {https://doi.org/10.1038/s41598-018-32621-w}, author = {Emily Smith-Woolley and Ayorech, Ziada and Philip S. Dale and Sophie von Stumm and Robert Plomin} } @article {235, title = {Genome-wide analysis of DNA methylation in buccal cells: a study of monozygotic twins and mQTLs}, journal = {Epigenetics {\&} Chromatin}, volume = {11}, year = {2018}, month = {Sep}, pages = {54}, abstract = {

DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA.

}, issn = {1756-8935}, doi = {10.1186/s13072-018-0225-x}, url = {https://doi.org/10.1186/s13072-018-0225-x}, author = {Jenny van Dongen and Ehli, Erik A. and Jansen, Rick and Catharina E. M. van Beijsterveldt and Gonneke Willemsen and Hottenga, Jouke J. and Kallsen, Noah A. and Peyton, Shanna A. and Breeze, Charles E. and Kluft, Cornelis and Bastiaan T. Heijmans and Meike Bartels and Gareth E Davies and Dorret I. Boomsma} } @article {262, title = {Monozygotic twin differences in school performance are stable and systematic}, journal = {Developmental Science}, volume = {21}, year = {2018}, pages = {e12694}, abstract = {

Abstract School performance is one of the most stable and heritable psychological characteristics. Notwithstanding, monozygotic twins (MZ), who have identical genotypes, differ in school performance. These MZ differences result from non-shared environments that do not contribute to the similarity within twin pairs. Because to date few non-shared environmental factors have been reliably associated with MZ differences in school performance, they are thought to be idiosyncratic and due to chance, suggesting that the effect of non-shared environments on MZ differences are age- and trait-specific. In a sample of 2768 MZ twin pairs, we found first that MZ differences in school performance were moderately stable from age 12 through 16, with differences at the ages 12 and 14 accounting for 20\% of the variance in MZ differences at age 16. Second, MZ differences in school performance correlated positively with MZ differences across 16 learning-related variables, including measures of intelligence, personality and school attitudes, with the twin who scored higher on one also scoring higher on the other measures. Finally, MZ differences in the 16 learning-related variables accounted for 22\% of the variance in MZ differences in school performance at age 16. These findings suggest that, unlike for other psychological domains, non-shared environmental factors affect school performance in systematic ways that have long-term and generalist influence. Our findings should motivate the search for non-shared environmental factors responsible for the stable and systematic effects on children\’s differences in school performance. A video abstract of this article can be viewed at: https://youtu.be/0bw2Fl\_HGq0

}, keywords = {difference scores, learning, Monozygotic twin, non-shared environment, school performance}, doi = {10.1111/desc.12694}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/desc.12694}, author = {Sophie von Stumm and Robert Plomin} } @article {276, title = {The new genetics of intelligence}, volume = {19}, year = {2018}, month = {08/2018}, pages = {148 - }, abstract = {

Intelligence - the ability to learn, reason and solve problems - is at the forefront of behavioural genetic research. Intelligence is highly heritable and predicts important educational, occupational and health outcomes better than any other trait. Recent genome-wide association studies have successfully identified inherited genome sequence differences that account for 20\% of the 50\% heritability of intelligence. These findings open new avenues for research into the causes and consequences of intelligence using genome-wide polygenic scores that aggregate the effects of thousands of genetic variants.

}, url = {https://doi.org/10.1038/nrg.2017.104}, author = {Robert Plomin and Sophie von Stumm} } @article {284, title = {Prenatal Maternal Stress and Child IQ}, journal = {Child Development}, year = {2018}, month = {10/2018}, abstract = {

The evidence for negative influences of maternal stress during pregnancy on child cognition remains inconclusive. This study tested the association between maternal prenatal stress and child intelligence in 4,251 mother\–child dyads from a multiethnic population-based cohort in the Netherlands. A latent factor of prenatal stress was constructed, and child IQ was tested at age 6\ years. In Dutch and Caribbean participants, prenatal stress was not associated with child IQ after adjustment for maternal IQ and socioeconomic status. In other ethnicities no association was found; only in the Moroccan/Turkish group a small negative association between prenatal stress and child IQ was observed. These results suggest that prenatal stress does not predict child IQ, except in children from less acculturated minority groups.

}, doi = {10.1111/cdev.13177}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/cdev.13177}, author = {Cortes Hidalgo, Andrea P. and Alexander Neumann and Marian J Bakermans-Kranenburg and Vincent W.V. Jaddoe and Rijlaarsdam, Jolien and Frank Verhulst and Tonya White and van IJzendoorn, Marinus H. and Henning Tiemeier} } @article {282, title = {Psychotic-like experiences in pre-adolescence: what precedes the antecedent symptoms of severe mental illness?}, journal = {Acta Psychiatrica Scandinavica}, volume = {138}, year = {2018}, pages = {15-25}, abstract = {

OBJECTIVE:

Adolescent psychotic-like experiences predict the onset of psychosis, but also predict subsequent non-psychotic disorders. Therefore, it is crucial to better understand the aetiology of psychotic-like experiences. This study examined whether (a) child emotional and behavioural problems at 3 and 6 years, or (b) childhood adversities were associated with psychotic-like experiences at age 10 years.

METHOD:

This prospective study was embedded in the Generation R Study; 3984 children (mean age 10 years) completed a psychotic-like experiences questionnaire. Mothers reported problems of their child at ages 3, 6 and 10 years. Additionally, mothers were interviewed about their child\&$\#$39;s adversities.

RESULTS:

Psychotic-like experiences were endorsed by ~20\% of children and predicted by both emotional and behavioural problems at 3 years (e.g. emotional-reactive problems: ORadjusted = 1.10, 95\% CI: 1.06-1.15, aggressive behaviour: ORadjusted = 1.03, 95\% CI: 1.02-1.05) and 6 years (e.g. anxious/depressed problems: ORadjusted = 1.11, 95\% CI: 1.06-1.15, aggressive behaviour: ORadjusted = 1.04, 95\% CI: 1.04-1.05). Childhood adversities were associated with psychotic-like experiences (\>2 adversities: ORadjusted = 2.24, 95\% CI: 1.72-2.92), which remained significant after adjustment for comorbid psychiatric problems.

CONCLUSION:

This study demonstrated associations between early adversities, childhood emotional and behavioural problems and pre-adolescent psychotic-like experiences, which will improve the understanding of children at increased risk of severe mental illness.

}, keywords = {childhood adversities, development, prospective, Psychosis, psychotic symptoms}, doi = {10.1111/acps.12891}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/acps.12891}, author = {Koen Bolhuis and Koopman-Verhoeff, M. E. and Blanken, L. M. E. and Cibrev, D. and Vincent W.V. Jaddoe and Frank Verhulst and Manon H.J. Hillegers and Steven A. Kushner and Henning Tiemeier} } @article {316, title = {Risk factors for parental psychopathology: a study in families with children or adolescents with psychopathology}, journal = {European Child \& Adolescent Psychiatry}, volume = {27}, year = {2018}, pages = {1575{\textendash}1584}, abstract = {

The parents of children with psychopathology are at increased risk for psychiatric symptoms. To investigate which parents are mostly at risk, we assessed in a clinical sample of families with children with psychopathology, whether parental symptom scores can be predicted by offspring psychiatric diagnoses and other child, parent and family characteristics. Parental depressive, anxiety, avoidant personality, attention-deficit/hyperactivity (ADHD), and antisocial personality symptoms were measured with the Adult Self Report in 1805 mothers and 1361 fathers of 1866 children with a psychiatric diagnosis as assessed in a child and adolescent psychiatric outpatient clinic. In a multivariate model, including all parental symptom scores as outcome variables, all offspring psychiatric diagnoses, offspring comorbidity and age, parental age, parental educational attainment, employment, and relationship status were simultaneously tested as predictors. Both 35.7\% of mothers and 32.8\% of fathers scored (sub)clinical for at least one symptom domain, mainly depressive symptoms, ADHD symptoms or, only in fathers, avoidant personality symptoms. Parental psychiatric symptoms were predicted by unemployment. Parental depressive and ADHD symptoms were further predicted by offspring depression and offspring ADHD, respectively, as well as by not living together with the other parent. Finally, parental avoidant personality symptoms were also predicted by offspring autism spectrum disorders. In families with children referred to child and adolescent psychiatric outpatient clinics, parental symptom scores are associated with adverse circumstances and with similar psychopathology in their offspring. This signifies, without implying causality, that some families are particularly vulnerable, with multiple family members affected and living in adverse circumstances.

}, keywords = {Childhood psychopathology, Family circumstances, parent-offspring associations, parental psychopathology, Risk factors}, doi = {10.1007/s00787-018-1156-6}, author = {Wesseldijk, L W and Dieleman, G C and van Steensel, F J A and Bartels, M and Hudziak, J J and Lindauer, R J L and B{\"o}gels, S M and Middeldorp, C M} } @article {283, title = {Unraveling the Genetic and Environmental Relationship Between Well-Being and Depressive Symptoms Throughout the Lifespan}, journal = {Frontiers in Psychiatry}, volume = {9}, year = {2018}, pages = {261}, abstract = {

Whether well-being and depressive symptoms can be considered as two sides of the same coin is widely debated. The aim of this study was to gain insight into the etiology of the association between well-being and depressive symptoms across the lifespan. In a large twin-design, including data from 43,427 twins between age 7 and 99, we estimated the association between well-being and depressive symptoms throughout the lifespan and assessed genetic and environmental contributions to the observed overlap. For both well-being (range 31\% \–47\%) and depressive symptoms (range 50\%-61\%), genetic factors explained a substantial part of the phenotypic variance across the lifespan. Phenotypic correlations between well-being and depressive symptoms across ages ranged from -.34 in childhood to -.49 in adulthood. In children, genetic effects explained 49\% of the phenotypic correlation while in adolescents and young adults, genetic effects explained 60\% to 77\% of the phenotypic correlations. Moderate to high genetic correlations (ranging from -0.60 to -0.66) were observed in adolescence and adulthood, while in childhood environmental correlations were substantial but genetic correlations small. Our results suggest that in childhood genetic and environmental effects are about equally important in explaining the relationship between well-being and depressive symptoms. From adolescence onwards, the role of genetic effects increases compared to environmental effects. These results provided more insights into the etiological underpinnings of well-being and depressive symptoms, possibly allowing to articulate better strategies for health promotion and resource allocation in the future.

}, issn = {1664-0640}, doi = {10.3389/fpsyt.2018.00261}, url = {https://www.frontiersin.org/article/10.3389/fpsyt.2018.00261}, author = {Bart M. L. Baselmans and Willems, Yayouk E. and Catharina E. M. van Beijsterveldt and Lannie Ligthart and Gonneke Willemsen and Conor V Dolan and Dorret I. Boomsma and Meike Bartels} } @article {314, title = {Why do children read more? The influence of reading ability on voluntary reading practices}, journal = {Journal of Child Psychology and Psychiatry}, volume = {59}, year = {2018}, pages = {1205{\textendash}1214}, abstract = {

BACKGROUND: This study investigates the causal relationships between reading and print exposure and investigates whether the amount children read outside school determines how well they read, or vice versa. Previous findings from behavioural studies suggest that reading predicts print exposure. Here, we use twin-data and apply the behaviour-genetic approach of direction of causality modelling, suggested by Heath et al. (), to investigate the causal relationships between these two traits.

METHOD: Partial data were available for a large sample of twin children (N = 11,559) and 262 siblings, all enrolled in the Netherlands Twin Register. Children were assessed around 7.5 years of age. Mothers completed questionnaires reporting children\&$\#$39;s time spent on reading activities and reading ability. Additional information on reading ability was available through teacher ratings and performance on national reading tests. For siblings reading test, results were available.

RESULTS: The reading ability of the twins was comparable to that of the siblings and national norms, showing that twin findings can be generalized to the population. A measurement model was specified with two latent variables, Reading Ability and Print Exposure, which correlated .41. Heritability analyses showed that Reading Ability was highly heritable, while genetic and environmental influences were equally important for Print Exposure. We exploited the fact that the two constructs differ in genetic architecture and fitted direction of causality models. The results supported a causal relationship running from Reading Ability to Print Exposure.

CONCLUSIONS: How much and how well children read are moderately correlated. Individual differences in print exposure are less heritable than individual differences in reading ability. Importantly, the present results suggest that it is the children\&$\#$39;s reading ability that determines how much they choose to read, rather than vice versa.

}, keywords = {behaviour-genetics, causal modelling, Direction of causality models, print exposure, reading skills, twin studies}, doi = {10.1111/jcpp.12910}, author = {van Bergen, Elsje and Snowling, Margaret J and de Zeeuw, Eveline L and van Beijsterveldt, Catharina E M and Dolan, Conor V and Boomsma, Dorret I} } @article {192, title = {Disentangling Heterogeneity of Childhood Disruptive Behavior Problems Into Dimensions and Subgroups}, journal = {American Academy of Child and Adolescent Psychiatry. Journal}, volume = {56}, year = {2017}, pages = {678{\textendash}686}, abstract = {

OBJECTIVE:

Irritable and oppositional behaviors are increasingly considered as distinct dimensions of oppositional defiant disorder. However, few studies have explored this multidimensionality across the broader spectrum of disruptive behavior problems (DBPs). This study examined the presence of dimensions and distinct subgroups of childhood DBPs, and the cross-sectional and longitudinal associations between these dimensions.

METHOD:

Using factor mixture models (FMMs), the presence of dimensions and subgroups of DBPs was assessed in the Generation R Study at ages 6 (n\ = 6,209) and 10 (n\ =\ 4,724) years. Replications were performed in two population-based cohorts (Netherlands Twin Registry, n\ = 4,402, and Swedish Twin Study of Child and Adolescent Development, n\ = 1,089) and a clinical sample (n\ = 1,933). We used cross-lagged modeling in the Generation R Study to assess cross-sectional and longitudinal associations between dimensions. DBPs were assessed using mother-reported responses to the Child Behavior Checklist.

RESULTS:

Empirically obtained dimensions of DBPs were oppositional behavior (age 6 years), disobedient behavior, rule-breaking behavior (age 10 years), physical aggression, and irritability (both ages). FMMs suggested that one-class solutions had the best model fit for all dimensions in all three population-based cohorts. Similar results were obtained in the clinical sample. All three dimensions, including irritability, predicted subsequent physical aggression (range, 0.08-0.16).

CONCLUSION:

This study showed that childhood DBPs should be regarded as a multidimensional phenotype rather than comprising distinct subgroups. Incorporating multidimensionality will improve diagnostic accuracy and refine treatment. Future studies need to address the biological validity of the DBP dimensions observed in this study; herein lies an important opportunity for neuroimaging and genetic measures.

}, doi = {10.1016/j.jaac.2017.05.019}, author = {Koen Bolhuis and Gitta Lubke and van der Ende, Jan and Meike Bartels and van Beijsterveldt, Toos and Paul Lichtenstein and Henrik Larsson and Vincent W.V. Jaddoe and Steven A. Kushner and Frank Verhulst and Dorret I. Boomsma and Henning Tiemeier} } @article {194, title = {Genetic and environmental influences on conduct and antisocial personality problems in childhood, adolescence, and adulthood}, journal = {European Child {\&} Adolescent Psychiatry}, year = {2017}, month = {Jun}, abstract = {

Conduct problems in children and adolescents can predict antisocial personality disorder and related problems, such as crime and conviction. We sought an explanation for such predictions by performing a genetic longitudinal analysis. We estimated the effects of genetic, shared environmental, and unique environmental factors on variation in conduct problems measured at childhood and adolescence and antisocial personality problems measured at adulthood and on the covariation across ages. We also tested whether these estimates differed by sex. Longitudinal data were collected in the Netherlands Twin Register over a period of 27\ years. Age appropriate and comparable measures of conduct and antisocial personality problems, assessed with the Achenbach System of Empirically Based Assessment, were available for 9783 9\–10-year-old, 6839 13\–18-year-old, and 7909 19\–65-year-old twin pairs, respectively; 5114 twins have two or more assessments. At all ages, men scored higher than women. There were no sex differences in the estimates of the genetic and environmental influences. During childhood, genetic and environmental factors shared by children in families explained 43 and 44{\%} of the variance of conduct problems, with the remaining variance due to unique environment. During adolescence and adulthood, genetic and unique environmental factors equally explained the variation. Longitudinal correlations across age varied between 0.20 and 0.38 and were mainly due to stable genetic factors. We conclude that shared environment is mainly of importance during childhood, while genetic factors contribute to variation in conduct and antisocial personality problems at all ages, and also underlie its stability over age.

}, issn = {1435-165X}, doi = {10.1007/s00787-017-1014-y}, url = {https://doi.org/10.1007/s00787-017-1014-y}, author = {Laura W. Wesseldijk and Meike Bartels and Vink, Jacqueline M. and Catharina E. M. van Beijsterveldt and Lannie Ligthart and Dorret I. Boomsma and Christel Middeldorp} } @article {193, title = {Heritability of Behavioral Problems in 7-Year Olds Based on Shared and Unique Aspects of Parental Views}, journal = {Behavior Genetics}, volume = {47}, year = {2017}, month = {Mar}, pages = {152{\textendash}163}, abstract = {

In studies of child psychopathology, phenotypes of interest are often obtained by parental ratings. When behavioral ratings are obtained in the context of a twin study, this allows for the decomposition of the phenotypic variance, into a genetic and a non-genetic part. If a phenotype is assessed by a single rater, heritability is based on the child\&$\#$39;s behavior as expressed in the presence of that particular rater, whereas heritability based on assessments by multiple raters allows for the estimation of the heritability of the phenotype based on rater agreement, as well as the heritability of the rater specific view of the behavior. The aim of this twin study was to quantify the rater\ common and rater specific contributions to the variation in children\&$\#$39;s behavioral problems. We estimated the heritability of maternal and paternal ratings of the Child Behavior Checklist (CBCL) 6\–18 empirical emotional and behavioral problem scales in a large sample of 12,310 7-year old Dutch twin pairs. Between 30 and 59{\%} of variation in the part of the phenotype parents agree upon was explained by genetic effects. Common environmental effects that make children in the same family similar explained less variance, ranging between 0 and 32{\%}. For unique views of their children\&$\#$39;s behavioral problems, heritability ranged between 0 and 20{\%} for maternal and between 0 and 22{\%} for paternal views. Between 7 and 24{\%} of the variance was accounted for by common environmental factors specific to mother and father\&$\#$39;s views. The proportion of rater shared and rater specific heritability can be translated into genetic correlations between parental views and inform the design and interpretation of results of molecular genetic studies. Genetic correlations were nearly or above 0.7 for all CBCL based psychopathology scales. Such large genetic correlations suggest two practical guidelines for genome-wide association studies (GWAS): when studies have collected data from either fathers or mothers, the shared genetic aetiology in parental ratings indicates that is possible to analyze paternal and maternal assessments in a single GWAS or meta-analysis. Secondly, if a study has collected information from both parents, a gain in statistical power may be realized in GWAS by the simultaneous analysis of the data.

}, issn = {1573-3297}, doi = {10.1007/s10519-016-9823-1}, url = {https://doi.org/10.1007/s10519-016-9823-1}, author = {Fedko, Iryna O. and Laura W. Wesseldijk and Michel G. Nivard and Hottenga, Jouke-Jan and Catharina E. M. van Beijsterveldt and Christel Middeldorp and Meike Bartels and Dorret I. Boomsma} } @article {291, title = {Multi-polygenic score approach to trait prediction}, volume = {23}, year = {2017}, month = {08/2017}, pages = {1368}, abstract = {

A primary goal of polygenic scores, which aggregate the effects of thousands of trait-associated DNA variants discovered in genome-wide association studies (GWASs), is to estimate individual-specific genetic propensities and predict outcomes. This is typically achieved using a single polygenic score, but here we use a multi-polygenic score (MPS) approach to increase predictive power by exploiting the joint power of multiple discovery GWASs, without assumptions about the relationships among predictors. We used summary statistics of 81 well-powered GWASs of cognitive, medical and anthropometric traits to predict three core developmental outcomes in our independent target sample: educational achievement, body mass index (BMI) and general cognitive ability. We used regularized regression with repeated cross-validation to select from and estimate contributions of 81 polygenic scores in a UK representative sample of 6710 unrelated adolescents. The MPS approach predicted 10.9\% variance in educational achievement, 4.8\% in general cognitive ability and 5.4\% in BMI in an independent test set, predicting 1.1\%, 1.1\%, and 1.6\% more variance than the best single-score predictions. As other relevant GWA analyses are reported, they can be incorporated in MPS models to maximize phenotype prediction. The MPS approach should be useful in research with modest sample sizes to investigate developmental, multivariate and gene\–environment interplay issues and, eventually, in clinical settings to predict and prevent problems using personalized interventions.

}, url = {https://doi.org/10.1038/mp.2017.163}, author = {Krapohl, E and Patel, H and Newhouse, S and Curtis, C J and von Stumm, S and Dale, P S and Zabaneh, D and Breen, G and O{\textquoteright}Reilly, P F and Plomin, R} } @article {202, title = {Personalized Media: A Genetically Informative Investigation of Individual Differences in Online Media Use}, journal = {PLOS ONE}, volume = {12}, year = {2017}, month = {01}, pages = {1-10}, abstract = {

Online media use has become an increasingly important behavioral domain over the past decade. However, studies into the etiology of individual differences in media use have focused primarily on pathological use. Here, for the first time, we test the genetic influences on online media use in a UK representative sample of 16 year old twins, who were assessed on time spent on educational (N = 2,585 twin pairs) and entertainment websites (N = 2,614 twin pairs), time spent gaming online (N = 2,635 twin pairs), and Facebook use (N = 4,333 twin pairs). Heritability was substantial for all forms of online media use, ranging from 34\% for educational sites to 37\% for entertainment sites and 39\% for gaming. Furthermore, genetics accounted for 24\% of the variance in Facebook use. Our results support an active model of the environment, where young people choose their online engagements in line with their genetic propensities.

}, doi = {10.1371/journal.pone.0168895}, url = {https://doi.org/10.1371/journal.pone.0168895}, author = {Ayorech, Ziada and Sophie von Stumm and Haworth, Claire M. A. and Davis, Oliver S. P. and Robert Plomin} } @article {199, title = {Predicting educational achievement from DNA}, journal = {Mol Psychiatry}, volume = {22}, year = {2017}, month = {2017/02//print}, pages = {267 - 272}, abstract = {

A genome-wide polygenic score (GPS), derived from a 2013 genome-wide association study (N=127,000), explained 2\% of the variance in total years of education (EduYears). In a follow-up study (N=329,000), a new EduYears GPS explains up to 4\%. Here, we tested the association between this latest EduYears GPS and educational achievement scores at ages 7, 12 and 16 in an independent sample of 5825 UK individuals. We found that EduYears GPS explained greater amounts of variance in educational achievement over time, up to 9\% at age 16, accounting for 15\% of the heritable variance. This is the strongest GPS prediction to date for quantitative behavioral traits. Individuals in the highest and lowest GPS septiles differed by a whole school grade at age 16. Furthermore, EduYears GPS was associated with general cognitive ability (~3.5\%) and family socioeconomic status (~7\%). There was no evidence of an interaction between EduYears GPS and family socioeconomic status on educational achievement or on general cognitive ability. These results are a harbinger of future widespread use of GPS to predict genetic risk and resilience in the social and behavioral sciences.

}, isbn = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2016.107}, author = {Saskia Selzam and Eva Krapohl and Sophie von Stumm and Paul F O{\textquoteright}Reilly and Kaili Rimfeld and Yulia Kovas and Philip S. Dale and Lee,J J and Robert Plomin} } @article {313, title = {Psychopathology in 7-year-old children: Differences in maternal and paternal ratings and the genetic epidemiology}, journal = {American Journal of Medical Genetics Part B: Neuropsychiatric Genetics}, volume = {174}, year = {2017}, pages = {251{\textendash}260}, abstract = {

The assessment of children\&$\#$39;s psychopathology is often based on parental report. Earlier studies have suggested that rater bias can affect the estimates of genetic, shared environmental and unique environmental influences on differences between children. The availability of a large dataset of maternal as well as paternal ratings of psychopathology in 7-year old children enabled (i) the analysis of informant effects on these assessments, and (ii) to obtain more reliable estimates of the genetic and non-genetic effects. DSM-oriented measures of affective, anxiety, somatic, attention-deficit/hyperactivity, oppositional-defiant, conduct, and obsessive-compulsive problems were rated for 12,310 twin pairs from the Netherlands Twin Register by mothers (N = 12,085) and fathers (N = 8,516). The effects of genetic and non-genetic effects were estimated on the common and rater-specific variance. For all scales, mean scores on maternal ratings exceeded paternal ratings. Parents largely agreed on the ranking of their child\&$\#$39;s problems (r 0.60-0.75). The heritability was estimated over 55\% for maternal and paternal ratings for all scales, except for conduct problems (44-46\%). Unbiased shared environmental influences, i.e., on the common variance, were significant for affective (13\%), oppositional (13\%), and conduct problems (37\%). In clinical settings, different cutoffs for (sub)clinical scores could be applied to paternal and maternal ratings of their child\&$\#$39;s psychopathology. Only for conduct problems, shared environmental and genetic influences explain an equal amount in differences between children. For the other scales, genetic factors explain the majority of the variance, especially for the common part that is free of rater bias. \copyright{} 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

}, keywords = {parental ratings, psychopathology, rater bias, shared environment, twins}, doi = {10.1002/ajmg.b.32500}, author = {Wesseldijk, Laura W and Fedko, Iryna O and Bartels, Meike and Nivard, Michel G and van Beijsterveldt, Catharina E M and Boomsma, Dorret I and Middeldorp, Christel M} } @article {211, title = {Selected Lectures of the 13th International Workshop on Neonatology. LECT 39, Self-reported aggressive behavior in humans and biomarkers: a focus on lipids and methylation}, journal = {Journal of Pediatric and Neonatal Individualized Medicine (JPNIM)}, volume = {6}, year = {2017}, month = {10/2017}, pages = {52-55}, type = {Proceedings of the 13{\textdegree} International Workshop on Neonatology, Twins: identical but different, Cagliari (Italy), October 25-28}, abstract = {

PDF Available here

}, keywords = {13th International Workshop on Neonatology, 2017, Aggression, Cagliari}, doi = {10.7363/060235}, url = {http://www.jpnim.com/index.php/jpnim/article/view/060235/467}, author = {Fiona Hagenbeek and Jenny van Dongen and Kluft, Cornelis and Lannie Ligthart} } @article {128, title = {Genetic and environmental influences interact with age and sex in shaping the human methylome}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016/04/07}, abstract = {

The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19\%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.

}, url = {http://dx.doi.org/10.1038/ncomms11115}, author = {Jenny van Dongen and Michel G. Nivard and Gonneke Willemsen and Hottenga, Jouke-Jan and Helmer, Quinta and Conor V Dolan and Ehli, Erik A. and Gareth E Davies and van Iterson, Maarten and Breeze, Charles E. and Beck, Stephan and BIOS Consortium and Suchiman, H. Eka and Jansen, Rick and Joyce B.J. Van Meurs and Bastiaan T. Heijmans and Slagboom, P. Eline and Dorret I. Boomsma} } @article {102, title = {Longitudinal heritability of childhood aggression.}, journal = {Am J Med Genet B Neuropsychiatr Genet}, year = {2016}, month = {2016 Jan 19}, abstract = {

The genetic and environmental contributions to the variation and longitudinal stability in childhood aggressive behavior were assessed in two large twin cohorts, the Netherlands Twin Register (NTR), and the Twins Early Development Study (TEDS; United Kingdom). In NTR, maternal ratings on aggression from the Child Behavior Checklist (CBCL) were available for 10,765 twin pairs at age 7, for 8,557 twin pairs at age 9/10, and for 7,176 twin pairs at age 12. In TEDS, parental ratings of conduct disorder from the Strength and Difficulty Questionnaire (SDQ) were available for 6,897 twin pairs at age 7, for 3,028 twin pairs at age 9 and for 5,716 twin pairs at age 12. In both studies, stability and heritability of aggressive behavioral problems was high. Heritability was on average somewhat, but significantly, lower in TEDS (around 60\%) than in NTR (between 50\% and 80\%) and sex differences were slightly larger in the NTR sample. In both studies, the influence of shared environment was similar: in boys shared environment explained around 20\% of the variation in aggression across all ages while in girls its influence was absent around age 7 and only came into play at later ages. Longitudinal genetic correlations were the main reason for stability of aggressive behavior. Individual differences in CBCL-Aggressive Behavior and SDQ-Conduct disorder throughout childhood are driven by a comparable but significantly different genetic architecture. \© 2016 Wiley Periodicals, Inc.

}, issn = {1552-485X}, doi = {10.1002/ajmg.b.32420}, author = {Porsch, Robert M and Christel Middeldorp and Cherny, Stacey S and Eva Krapohl and Catharina E. M. van Beijsterveldt and Loukola, Anu and Korhonen, Tellervo and Pulkkinen, Lea and Corley, Robin and Rhee, Soo and Kaprio, Jaakko and Rose, Richard R and Hewitt, John K and Sham, Pak and Robert Plomin and Dorret I. Boomsma and Meike Bartels} } @article {257, title = {Role of overlapping genetic and environmental factors in the relationship between early adolescent conduct problems and substance use in young adulthood}, journal = {Addiction (Abingdon, England)}, volume = {111}, year = {2016}, month = {2016/06/}, pages = {1036 - 1045}, abstract = {

AIMS: To determine (1) the prospective associations of conduct problems during early adolescence with tobacco, alcohol and cannabis use in young adulthood and (2) to what extent these associations are due to overlapping genetic versus environmental influences. DESIGN: A prospective twin study using biometric twin modelling. SETTING: Finland. PARTICIPANTS: A total of 1847 Finnish twins (943 males and 904 females) were interviewed in early adolescence, 73\% of whom (n\ =\ 1353, 640 males and 713 females) were retained in young adulthood. MEASUREMENTS: Symptom counts of conduct disorder (CD) criteria were obtained from a semi-structured clinical interview in early adolescence [age 14-15 years, mean\ =\ 14.2, standard deviation (SD)\ =\ 0.15]. Frequency of alcohol, tobacco and cannabis use was obtained from a semi-structured clinical interview in young adulthood (age 19.9-26.6 years, mean\ =\ 22.4, SD\ =\ 0.7). FINDINGS: We found modest to moderate phenotypical correlations (r\ =\ 0.16-0.35) between early adolescent CD symptoms and substance use in young adulthood. In males, the phenotypical correlations of CD symptoms with all three substance use variables are explained largely by overlapping genetic influences. In females, overlapping shared environmental influences predominantly explain the phenotypical correlation between CD symptoms and tobacco and cannabis use. CONCLUSIONS: Conduct disorder symptoms in early adolescence appear to moderately predict substance use in early adulthood. In males, genetic influences seem to be most important in explaining the relationship between conduct disorder symptoms and substance use whereas in females, shared environmental influences seem to be most important.

}, isbn = {1360-04430965-2140}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26748618}, author = {Verweij, Karin J H and Creemers, Hanneke E and Korhonen, Tellervo and Latvala, Antti and Dick, Danielle M and Richard J. Rose and Huizink, Anja C and Kaprio, Jaakko} } @article {94, title = {Epigenome-Wide Association Study of Aggressive Behavior}, journal = {Twin Research and Human Genetics}, volume = {FirstView}, year = {2015}, month = {11}, pages = {1{\textendash}13}, issn = {1839-2628}, doi = {10.1017/thg.2015.74}, url = {http://journals.cambridge.org/article_S1832427415000742}, author = {Jenny van Dongen and Michel G. Nivard and Bart M. L. Baselmans and Zilh{\~a}o,Nuno R. and Lannie Ligthart and Bastiaan T. Heijmans and Meike Bartels and Dorret I. Boomsma} } @article {101, title = {A genome-wide approach to children{\textquoteright}s aggressive behavior: The EAGLE consortium.}, journal = {Am J Med Genet B Neuropsychiatr Genet}, year = {2015}, month = {2015 Jun 18}, abstract = {

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children\&$\#$39;s aggressive behavior to date (N\ =\ 18,988), with measures in two developmental stages (N\ =\ 15,668 early childhood and N\ =\ 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children\&$\#$39;s aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54\%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P\ =\ 5.30\ \×\ 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. \© 2015 Wiley Periodicals, Inc.

}, issn = {1552-485X}, doi = {10.1002/ajmg.b.32333}, author = {Pappa, Irene and St Pourcain, Beate and Benke, Kelly and Cavadino, Alana and Hakulinen, Christian and Michel G. Nivard and Nolte, Ilja M and Tiesler, Carla M T and Marian J Bakermans-Kranenburg and Gareth E Davies and David M Evans and Geoffroy, Marie-Claude and Grallert, Harald and Groen-Blokhuis, Maria M and J.J. Hudziak and Kemp, John P and Keltikangas-J{\"a}rvinen, Liisa and McMahon, George and Mileva-Seitz, Viara R and Motazedi, Ehsan and Power, Christine and Raitakari, Olli T and Ring, Susan M and Rivadeneira, Fernando and Rodriguez, Alina and Scheet, Paul A and Sepp{\"a}l{\"a}, Ilkka and Snieder, Harold and Standl, Marie and Thiering, Elisabeth and Timpson, Nicholas J and Veenstra, Ren{\'e} and Velders, Fleur P and Whitehouse, Andrew J O and Smith, George Davey and Heinrich, Joachim and Hypponen, Elina and Lehtim{\"a}ki, Terho and Christel Middeldorp and Oldehinkel, Albertine J and Pennell, Craig E and Dorret I. Boomsma and Henning Tiemeier} } @article {95, title = {Methylation as an epigenetic source of random genetic effects in the classical twin design}, journal = {Advances in Genomics and Genetics, Dove Medical Press}, volume = {5}, year = {2015}, month = {09/2015}, pages = {305{\textendash}315}, abstract = {

The epigenetic effects of cytosine methylation on gene expression are an acknowledged source of phenotypic variance. The discordant monozygotic (MZ) twin design has been used to demonstrate the role of methylation in disease. Application of the classical twin design, featuring both monozygotic and dizygotic twins, has demonstrated that individual differences in methylation levels are attributable to genetic and environmental (including stochastic) factors, with the latter explaining most of the variance. What implications epigenetic sources of variance have for the twin modeling of (non-epigenetic) phenotypes such as height and IQ is an open question. One possibility is that epigenetic effects are absorbed by the variance component attributable to unshared environmental. Another possibility is that such effects form an independent source of variance distinguishable in principle from standard genetic and environmental sources. In the present paper, we conceptualized epigenetic processes as giving rise to randomness in the effects of polygenetic influences. This means that the regression coefficient in the regression of the phenotype on the polygenic factor, as specified in the twin model, varies over individuals. We investigate the consequences of ignoring this randomness in the standard twin model.

}, keywords = {classical twin design, epigenetics, heritability, methylation, parameter randomness}, doi = {http://dx.doi.org/10.2147/AGG.S46909}, url = {https://www.dovepress.com/methylation-as-an-epigenetic-source-of-random-genetic-effects-in-the-c-peer-reviewed-article-AGG}, author = {Conor V Dolan and Michel G. Nivard and Jenny van Dongen and van der Sluis,Sophie and Dorret I. Boomsma} } @article {100, title = {Out of Control Identifying the Role of Self-Control Strength in Family Violence}, journal = {Current Directions in Psychological Science}, volume = {24}, year = {2015}, pages = {261{\textendash}266}, abstract = {

Family violence is common and brings tremendous costs to individuals, relationships, and society. Victims are vulnerable to negative outcomes across a host of dimensions, including cognitive performance, impulse control, emotion regulation, and physical health. Links between family violence and various problems have been established, yet the specific processes underlying these associations are poorly understood, resulting in the stunted development of effective interventions. This article addresses two key questions: How and why does family violence cause these myriad problems? The self-control strength model of family violence provides novel answers. The model integrates components of existing theories, extending them by pinpointing self-control strength as an explanatory and predictive factor, and can serve as a framework for interventions.

}, doi = {10.1177/0963721415570730}, url = {http://cdp.sagepub.com/content/24/4/261.abstract}, author = {Catrin Finkenauer and Buyukcan-Tetik, Asuman and Baumeister, Roy F and Schoemaker, Kim and Meike Bartels and Vohs, Kathleen D} }