@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 {368, title = {Discovery of 42 genome-wide significant loci associated with dyslexia}, journal = {Nature Genetics}, volume = {54}, year = {2022}, pages = {1621{\textendash}1629}, abstract = {

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70\%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6\% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.

}, doi = {10.1038/s41588-022-01192-y}, author = {Doust, Catherine and Fontanillas, Pierre and Eising, Else and Gordon, Scott D and Wang, Zhengjun and Alag{\"o}z, G{\"o}kberk and Molz, Barbara and 23andMe Research Team and Quantitative Trait Working Group of the GenLang Consortium and Pourcain, Beate St and Francks, Clyde and Marioni, Riccardo E and Zhao, Jingjing and Paracchini, Silvia and Talcott, Joel B and Monaco, Anthony P and Stein, John F and Gruen, Jeffrey R and Olson, Richard K and Willcutt, Erik G and DeFries, John C and Pennington, Bruce F and Smith, Shelley D and Wright, Margaret J and Martin, Nicholas G and Auton, Adam and Bates, Timothy C and Fisher, Simon E and Luciano, Michelle} } @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 {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 {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 {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 {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 {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 {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 {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 {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 {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 {344, title = {Robust longitudinal multi-cohort results: The development of self-control during adolescence}, journal = {Developmental Cognitive Neuroscience}, volume = {45}, year = {2020}, pages = {100817}, abstract = {

Longitudinal data from multiple cohorts may be analyzed by Bayesian research synthesis. Here, we illustrate this approach by investigating the development of self-control between age 13 and 19 and the role of sex therein in a multi-cohort, longitudinal design. Three Dutch cohorts supplied data: the Netherlands Twin Register (NTR; N = 21,079), Research on Adolescent Development and Relationships-Young (RADAR-Y; N = 497), and Tracking Adolescents\&$\#$39; Individual Lives Survey (TRAILS; N = 2229). Self-control was assessed by one measure in NTR and RADAR-Y, and three measures in TRAILS. In each cohort, we evaluated evidence for competing informative hypotheses regarding the development of self-control. Subsequently, we aggregated this evidence over cohorts and measures to arrive at a robust conclusion that was supported by all cohorts and measures. We found robust evidence for the hypothesis that on average self-control increases during adolescence (i.e., maturation) and that individuals with lower initial self-control often experience a steeper increase in self-control (i.e., a pattern of recovery). From self-report, boys have higher initial self-control levels at age 13 than girls, whereas parents report higher self-control for girls.

}, keywords = {Informative hypotheses, Longitudinal analysis, Research synthesis, self-control, Sex differences}, doi = {10.1016/j.dcn.2020.100817}, author = {Zondervan-Zwijnenburg, M A J and Richards, J S and Kevenaar, S T and Becht, A I and Hoijtink, H J A and Oldehinkel, A J and Branje, S and Meeus, W and Boomsma, D 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 {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 {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 {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 {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 {271, title = {Evidence for gene-environment correlation in child feeding: Links between common genetic variation for BMI in children and parental feeding practices}, journal = {PLOS Genetics}, volume = {14}, year = {2018}, month = {11}, pages = {1-19}, abstract = {

The parental feeding practices (PFPs) of excessive restriction of food intake (\‘restriction\’) and pressure to increase food consumption (\‘pressure\’) have been argued to causally influence child weight in opposite directions (high restriction causing overweight; high pressure causing underweight). However child weight could also \‘elicit\’ PFPs. A novel approach is to investigate gene-environment correlation between child genetic influences on BMI and PFPs. Genome-wide polygenic scores (GPS) combining BMI-associated variants were created for 10,346 children (including 3,320 DZ twin pairs) from the Twins Early Development Study using results from an independent genome-wide association study meta-analysis. Parental \‘restriction\’ and \‘pressure\’ were assessed using the Child Feeding Questionnaire. Child BMI standard deviation scores (BMI-SDS) were calculated from children\’s height and weight at age 10. Linear regression and fixed family effect models were used to test between- (n = 4,445 individuals) and within-family (n = 2,164 DZ pairs) associations between the GPS and PFPs. In addition, we performed multivariate twin analyses (n = 4,375 twin pairs) to estimate the heritabilities of PFPs and the genetic correlations between BMI-SDS and PFPs. The GPS was correlated with BMI-SDS (β = 0.20, p = 2.41x10-38). Consistent with the gene-environment correlation hypothesis, child BMI GPS was positively associated with \‘restriction\’ (β = 0.05, p = 4.19x10-4), and negatively associated with \‘pressure\’ (β = -0.08, p = 2.70x10-7). These results remained consistent after controlling for parental BMI, and after controlling for overall family contributions (within-family analyses). Heritabilities for \‘restriction\’ (43\% [40\–47\%]) and \‘pressure\’ (54\% [50\–59\%]) were moderate-to-high. Twin-based genetic correlations were moderate and positive between BMI-SDS and \‘restriction\’ (rA = 0.28 [0.23\–0.32]), and substantial and negative between BMI-SDS and \‘pressure\’ (rA = -0.48 [-0.52 - -0.44]. Results suggest that the degree to which parents limit or encourage children\’s food intake is partly influenced by children\’s genetic predispositions to higher or lower BMI. These findings point to an evocative gene-environment correlation in which heritable characteristics in the child elicit parental feeding behaviour.

}, doi = {10.1371/journal.pgen.1007757}, url = {https://doi.org/10.1371/journal.pgen.1007757}, author = {Saskia Selzam and McAdams, Tom A. and Jonathan R I Coleman and Carnell, Susan and Paul F O{\textquoteright}Reilly and Robert Plomin and Llewellyn, Clare H.} } @article {200, title = {Genome-Wide Polygenic Scores Predict Reading Performance Throughout the School Years}, journal = {Scientific Studies of Reading}, volume = {21}, year = {2017}, month = {2017/07/04}, pages = {334 - 349}, abstract = {

It is now possible to create individual-specific genetic scores, called genome-wide polygenic scores (GPS). We used a GPS for years of education (EduYears) to predict reading performance assessed at UK National Curriculum Key Stages 1 (age 7), 2 (age 12) and 3 (age 14) and on reading tests administered at ages 7 and 12 in a UK sample of 5,825 unrelated individuals. EduYears GPS accounts for up to 5\% of the variance in reading performance at age 14. GPS predictions remained significant after accounting for general cognitive ability and family socioeconomic status. Reading performance of children in the lowest and highest 12.5\% of the EduYears GPS distribution differed by a mean growth in reading ability of approximately two school years. It seems certain that polygenic scores will be used to predict strengths and weaknesses in education.

}, isbn = {1088-84381532-799X}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490720/}, author = {Saskia Selzam and Philip S. Dale and Wagner, Richard K and John C DeFries and Cederl{\"o}f, Martin and Paul F O{\textquoteright}Reilly and Eva Krapohl and Robert Plomin} } @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 {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 {270, title = {Widespread covariation of early environmental exposures and trait-associated polygenic variation}, journal = {Proceedings of the National Academy of Sciences}, volume = {114}, year = {2017}, pages = {11727{\textendash}11732}, abstract = {

Environmental exposures are among the best predictors of health and educational outcomes. Models that estimate the effect of environmental exposures on developmental outcomes typically ignore genetic factors or focus on gene\–environment interaction (whether individuals\’ response to environmental exposures depends on their genotype). Here we test gene\–environment correlation (whether individuals\’ exposure to environments depends on their genotype). Using a method that tests specific genetic effects while controlling for background genetic effects, we estimate covariation between children\’s genetic liability/propensity for core developmental outcomes and a wide range of environmental exposures. Findings suggest that genetic variants associated with traits, such as educational attainment, body mass index, and schizophrenia, also capture environmental risk and protective factors.Although gene\–environment correlation is recognized and investigated by family studies and recently by SNP-heritability studies, the possibility that genetic effects on traits capture environmental risk factors or protective factors has been neglected by polygenic prediction models. We investigated covariation between trait-associated polygenic variation identified by genome-wide association studies (GWASs) and specific environmental exposures, controlling for overall genetic relatedness using a genomic relatedness matrix restricted maximum-likelihood model. In a UK-representative sample (n = 6,710), we find widespread covariation between offspring trait-associated polygenic variation and parental behavior and characteristics relevant to children\’s developmental outcomes\—independently of population stratification. For instance, offspring genetic risk for schizophrenia was associated with paternal age (R2 = 0.002; P = 1e-04), and offspring education-associated variation was associated with variance in breastfeeding (R2 = 0.021; P = 7e-30), maternal smoking during pregnancy (R2 = 0.008; P = 5e-13), parental smacking (R2 = 0.01; P = 4e-15), household income (R2 = 0.032; P = 1e-22), watching television (R2 = 0.034; P = 5e-47), and maternal education (R2 = 0.065; P = 3e-96). Education-associated polygenic variation also captured covariation between environmental exposures and children\’s inattention/hyperactivity, conduct problems, and educational achievement. The finding that genetic variation identified by trait GWASs partially captures environmental risk factors or protective factors has direct implications for risk prediction models and the interpretation of GWAS findings.

}, issn = {0027-8424}, doi = {10.1073/pnas.1707178114}, url = {https://www.pnas.org/content/114/44/11727}, author = {Eva Krapohl and Hannigan, L. J. and Pingault, J.-B. and Patel, H. and Kadeva, N. and Curtis, C. and Breen, G. and Newhouse, S. J. and Thalia C. Eley and Paul F O{\textquoteright}Reilly and Robert Plomin} } @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} }