Epigenome-Wide Association Study of Aggressive Behavior

Abstract

Aggressive behavior is highly heritable, while environmental influences, particularly early in life, are also important. Epigenetic mechanisms, such as DNA methylation, regulate gene expression throughout development and adulthood, and may mediate genetic and environmental effects on complex traits. We performed an epigenome-wide association study (EWAS) to identify regions in the genome where DNA methylation level is associated with aggressive behavior. Subjects took part in longitudinal survey studies from the Netherlands Twin Register (NTR) and participated in the NTR biobank project between 2004 and 2011 (N = 2,029, mean age at blood sampling = 36.4 years, SD = 12.4, females = 69.2%). Aggressive behavior was rated with the ASEBA Adult Self-Report (ASR). DNA methylation was measured in whole blood by the Illumina HM450k array. The association between aggressive behavior and DNA methylation level at 411,169 autosomal sites was tested. Association analyses in the entire cohort showed top sites at cg01792876 (chr8; 116,684,801, nearest gene = TRPS1, p = 7.6 × 10 −7 , False discovery rate (FDR) = 0.18) and cg06092953 (chr18; 77,905,699, nearest gene = PARD6G-AS1, p = 9.0 ×10 −7 , FDR = 0.18). Next, we compared methylation levels in 20 pairs of monozygotic (MZ) twins highly discordant for aggression. Here the top sites were cg21557159 (chr 11; 107,795,699, nearest gene = RAB39, p = 5.7 × 10 −6 , FDR = 0.99), cg08648367 (chr 19; 51,925,472, nearest gene = SIGLEC10, p = 7.6 × 10 −6 , FDR = 0.99), and cg14212412 (chr 6; 105,918,992, nearest gene = PREP, p = 8.0 × 10 −6 , FDR = 0.99). The two top hits based on the entire cohort showed the same direction of effect in discordant MZ pairs (cg01792876, P discordant twins = 0.09 and cg06092953, P discordant twins = 0.24). The other way around, two of the three most significant sites in discordant MZ pairs showed the same direction of effect in the entire cohort (cg08648367, P entire EWAS = 0.59 and cg14212412, P entire EWAS = 3.1 × 10 −3 ). Gene ontology analysis highlighted significant enrichment of various central nervous system categories among higher-ranking methylation sites. Higher-ranking methylation sites also showed enrichment for DNase I hypersensitive sites and promoter regions, showing that DNA methylation in peripheral tissues is likely to be associated with aggressive behavior.

DRD4 methylation as a potential biomarker for physical aggression: An epigenome‐wide, cross‐tissue investigation

“…Another set of enriched pathways related to inflammatory processes, including “cytokine secretion.” This is in line with reported alterations in DNAm and expression levels of cytokine genes in individuals with a chronic history of childhood physical aggression (Provençal, Suderman, Caramaschi, et al, ; Provencal, Suderman, Vitaro, Szyf, & Tremblay, ), as well as in individuals diagnosed with IED (Montalvo‐Ortiz et al, ). We also identified enrichment for multiple CNS‐related processes, such as “Axon guidance.” Interestingly, this same GO pathway was found to be highly enriched in the EWAS study on global aggression by van Dongen et al () as well as a recent bioinformatic analysis combining findings from six GWAS studies on aggression‐related phenotypes (Fernàndez‐Castillo & Cormand, ). Finally, we observed enrichment for regulation of “behavior,” which was again reported in the EWAS by van Dongen et al () in a general population of twins, but also in the EWAS by Guillemin et al () in adults following a chronic versus low trajectory of physical aggression in childhood.…”

“…We also identified enrichment for multiple CNS‐related processes, such as “Axon guidance.” Interestingly, this same GO pathway was found to be highly enriched in the EWAS study on global aggression by van Dongen et al () as well as a recent bioinformatic analysis combining findings from six GWAS studies on aggression‐related phenotypes (Fernàndez‐Castillo & Cormand, ). Finally, we observed enrichment for regulation of “behavior,” which was again reported in the EWAS by van Dongen et al () in a general population of twins, but also in the EWAS by Guillemin et al () in adults following a chronic versus low trajectory of physical aggression in childhood. In summary, our findings point to an “epigenetic signature” of physical aggression in buccal cells that is enriched for numerous biological processes, spanning neural, hormonal, immune and behavioral domains.…”

“…Of interest, several of these genes related to biological processes that have been previously implicated in physical aggression, including monoamine neurotransmission, neuroendocrine function, and inflammatory response (Provençal, Booij, & Tremblay, ). Besides this sample, one other study (van Dongen et al, ) based on a general population sample of over 2,000 adult twins examined epigenome‐wide associations between DNAm (extracted from whole blood at mean age = 36.4 years) and a global measure of aggressive behavior (i.e., not specifically related to physical aggression, but also including social and verbal aggression). None of the DNAm sites were found to associate with aggressive behavior after multiple correction, which the authors suggested may have been due to low rates of more severe forms of aggression (i.e., physical aggression).…”

Epigenetics, Representation, and Society

“…The impact of epigenetics is not limited to various developmental, physiological, hereditary, and other phenomena but extends to the biological dimension of animal and human behavior (van Dongen et al. , 686–95; Lenkov et al. , 1–9; Simola et al.…”

mCSEA: Detecting subtle differentially methylated regions

“…However, these tools may fail to detect significant DMRs in complex diseases or heterogeneous phenotypes, where there might be small differences among methylation signals but consistent across the analyzed regions and samples. Therefore, no individual CpGs or regions may meet the threshold for statistical significance in many studies, although there may be biologically meaningful differences (see for example Bohlin et al, 2015;Chiavaroli et al, 2015;van Dongen et al, 2015;Gervin et al, 2012;Kim et al, 2017).…”