@unpublished {383, title = {Longitudinal multi-omics study reveals common etiology underlying association between plasma proteome and BMI trajectories in adolescent and young adult twins}, journal = { medRxiv}, year = {2023}, abstract = {

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

}, doi = {10.1101/2023.06.28.23291995}, author = {Drouard, Gabin and Hagenbeek, Fiona A and Whipp, Alyce and Pool, Ren{\'e} and Hottenga, Jouke-Jan and Jansen, Rick and Hubers, Nikki and Afonin, Aleksei and Willemsen, Gonneke and de Geus, Eco J C and Ripatti, Samuli and Pirinen, Matti and Kanninen, Katja M and Boomsma, Dorret I and van Dongen, Jenny and Kaprio, Jaakko and BIOS Consortium and BBMRI-NL Metabolomics Consortium} } @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 {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 {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 {320, title = {Epigenome-wide association study of attention-deficit/hyperactivity disorder symptoms in adults}, journal = {Biological Psychiatry}, volume = {86}, year = {2019}, pages = {599{\textendash}607}, abstract = {

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

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

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

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

}, keywords = {ADHD, CAARS, DNA methylation, Epigenetic, EWAS, Meta-analysis}, doi = {10.1016/j.biopsych.2019.02.016}, author = {van Dongen, Jenny and Zilh{\~a}o, Nuno R and Sugden, Karen and BIOS Consortium and Hannon, Eilis J and Mill, Jonathan and Caspi, Avshalom and Agnew-Blais, Jessica and Arseneault, Louise and Corcoran, David L and Moffitt, Terrie E and Poulton, Richie and Franke, Barbara and Boomsma, Dorret I} } @article {128, title = {Genetic and environmental influences interact with age and sex in shaping the human methylome}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016/04/07}, abstract = {

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

}, url = {http://dx.doi.org/10.1038/ncomms11115}, author = {Jenny van Dongen and Michel G. Nivard and Gonneke Willemsen and Hottenga, Jouke-Jan and Helmer, Quinta and Conor V Dolan and Ehli, Erik A. and Gareth E Davies and van Iterson, Maarten and Breeze, Charles E. and Beck, Stephan and BIOS Consortium and Suchiman, H. Eka and Jansen, Rick and Joyce B.J. Van Meurs and Bastiaan T. Heijmans and Slagboom, P. Eline and Dorret I. Boomsma} }