Abstract
Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The 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 (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs 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 left| {r_g} right|: 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 left| {r_g} right|: 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
Highlights
There is a variety of phenotypic definitions of aggressive behavior (AGG), from broadly defined externalizing problems to narrow definitions like chronic physical aggression [1]
genome-wide association studies (GWASs) were run by local analysts following a standard operation protocol after which the summary statistics were uploaded to a central location for the meta-analysis
We present the largest genome-wide association metaanalysis (GWAMA) of childhood AGG to date
Summary
There is a variety of phenotypic definitions of aggressive behavior (AGG), from broadly defined externalizing problems to narrow definitions like chronic physical aggression [1]. Children typically display AGG early in life, after which symptoms tend to diminish [6, 7], in some individuals AGG persists into adulthood [8]. Childhood AGG co-occurs with many other behavioral, emotional, and social problems [15, 16] and is associated with increased risk of developing negative outcomes later in life, including cannabis abuse [17], criminal convictions [18], anxiety disorder [19], or antisocial personality disorder [20]. Children who learn to control their impulses and apply aggressive acts as a well-timed coercion strategy are generally more liked by their peers and score higher on social dominance [22]
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