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.

Identical twins carry a persistent epigenetic signature of early genome programming

“…Replication analyses were carried out in four cohorts (replication cohorts) with whole blood DNA methylation data available in adults: the UK Adult Twin Registry 54 (TwinsUK, Illumina 450k array), the Environmental Risk Longitudinal Twin Study 55 (E-Risk, Illumina 450k array), the Finnish Twin cohort 56 (FTC, Illumina 450k and EPIC array), and the Brisbane Systems Genetics Study 57,58 (BSGS, Illumina 450k array). A cross-tissue replication analysis was carried out in an independent cohort of children from the NTR (NTR-ACTION) with DNA methylation measured in buccal cells with the Illumina EPIC array 59 . Epigenomewide significance was assessed using Bonferroni correction for the number of sites tested (0.05/411169; alpha = 1.20 × 10 −7 ).…”

Predicting Complex Traits and Exposures From Polygenic Scores and Blood and Buccal DNA Methylation Profiles

“…DNA samples in adult twins and family members were isolated from whole blood DNA data and in twin children from buccal cells. Adults took part in the NTR-Biobank ( 32 ) and children in the FP7-Action project ( 33 – 36 ). The study was approved by the Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Centre, Amsterdam, an Institutional Review Board certified by the U.S. Office of Human Research Protections (IRB number IRB00002991 under Federal-wide Assurance FWA00017598; IRB/institute codes, NTR 03-180).…”

“…The mean age at DNA collection was 9.6 years (range = 5.6–12.9 years) and 52.8% were males. For 2 participants, a technical replicate measure on with the Infinium MethylationEPIC BeadChip Kit was included ( 36 ). Individuals without missing data on phenotypes or covariates were included in the analyses, and phenotype outliers were excluded, resulting in a sample size of 1,070 children for birth weight and 1,072 for BMI.…”

“…DNA methylation was assessed with the Infinium MethylationEPIC BeadChip Kit (Illumina, San Diego, CA, USA) by the Human Genotyping facility (HugeF) of ErasmusMC, the Netherlands ( http://www.glimdna.org/ ) [see van Dongen et al ( 36 )]. Quality control (QC) and normalization of the methylation data were performed using a pipeline developed by the Biobank-based Integrative Omics Study (BIOS) consortium ( 43 ), which includes sample quality control using the R package MethylAid ( 39 ) and probe filtering and functional normalization ( 42 ) as implemented in the R package DNAmArray.…”

Epigenome-wide association study of left-handedness for different tissues and ages

“…DNA samples were collected from buccal swabs, as previously described 89 . DNA methylation was measured using the In nium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) 90 , wet laboratory procedure, preprocessing analyses, and quality control were performed by the Human Genotyping facility (HugeF) of ErasmusMC, the Netherlands (http://www.glimdna.org/), as previously described 91 . Only autosomal methylation sites were analyzed, leaving 787,711 out of 865,859 sites for analysis.…”