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DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

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 × 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 = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

SUBMITTER: van Dongen J

PROVIDER: S-EPMC8263810 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

van Dongen Jenny J Hagenbeek Fiona A FA Suderman Matthew M Roetman Peter J PJ Sugden Karen K Chiocchetti Andreas G AG Ismail Khadeeja K Mulder Rosa H RH Hafferty Jonathan D JD Adams Mark J MJ Walker Rosie M RM Morris Stewart W SW Lahti Jari J Küpers Leanne K LK Escaramis Georgia G Alemany Silvia S Jan Bonder Marc M Meijer Mandy M Ip Hill F HF Jansen Rick R Baselmans Bart M L BML Parmar Priyanka P Lowry Estelle E Streit Fabian F Sirignano Lea L Send Tabea S TS Frank Josef J Jylhävä Juulia J Wang Yunzhang Y Mishra Pashupati Prasad PP Colins Olivier F OF Corcoran David L DL Poulton Richie R Mill Jonathan J Hannon Eilis E Arseneault Louise L Korhonen Tellervo T Vuoksimaa Eero E Felix Janine F JF Bakermans-Kranenburg Marian J MJ Campbell Archie A Czamara Darina D Binder Elisabeth E Corpeleijn Eva E Gonzalez Juan R JR Grazuleviciene Regina R Gutzkow Kristine B KB Evandt Jorunn J Vafeiadi Marina M Klein Marieke M van der Meer Dennis D Ligthart Lannie L Kluft Cornelis C Davies Gareth E GE Hakulinen Christian C Keltikangas-Järvinen Liisa L Franke Barbara B Freitag Christine M CM Konrad Kerstin K Hervas Amaia A Fernández-Rivas Aranzazu A Vetro Agnes A Raitakari Olli O Lehtimäki Terho T Vermeiren Robert R Strandberg Timo T Räikkönen Katri K Snieder Harold H Witt Stephanie H SH Deuschle Michael M Pedersen Nancy L NL Hägg Sara S Sunyer Jordi J Franke Lude L Kaprio Jaakko J Ollikainen Miina M Moffitt Terrie E TE Tiemeier Henning H van IJzendoorn Marinus H MH Relton Caroline C Vrijheid Martine M Sebert Sylvain S Jarvelin Marjo-Riitta MR Caspi Avshalom A Evans Kathryn L KL McIntosh Andrew M AM Bartels Meike M Boomsma Dorret I DI

Molecular psychiatry 20210108 6

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 ...[more]

PMID: 33420481

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Project description:ImportanceDepressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers.ObjectiveTo identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood.Design, setting, and participantsTo date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts.Main outcomes and measuresWhole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire.ResultsThe discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10-04) was associated with major depression.Conclusions and relevanceThis study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.

Project description:BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10-4; adolescence Penrichment = 2.10 × 10-7).ConclusionsThere were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.

Dataset Information

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

Publications

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

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