Genetic Association Study of Childhood Aggression across raters, instruments and age

Abstract

Background Human aggressive behavior (AGG) has a substantial genetic component. Here we present a large genome-wide association meta-analysis (GWAMA) of childhood AGG. Methods We analyzed assessments of AGG for a total of 328,935 observations from 87,485 children (aged 1.5 – 18 years), from multiple assessors, instruments, and ages, while accounting for sample overlap. We performed an overall analysis and meta-analyzed subsets of the data within rater, instrument, and age. Results Heritability based on the overall meta-analysis (AGGall) that could be attributed to Single Nucleotide Polymorphisms (SNPs) was 3.31% (SE=0.0038). No single SNP reached genome-wide significance, but 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 and in retrospectively assessed childhood aggression. We obtained moderate-to-strong genetic correlations (rg‘s) 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 |rg|: 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 |rg|: 0.46 – 0.60). Genetic correlations between AGG and psychiatric disorders were strongest for mother- and self-reported AGG. Conclusions The current GWAMA of childhood aggression provides a powerful tool to interrogate the genetic etiology of AGG by creating individual polygenic scores and genetic correlations with psychiatric traits.