Genetic association study of childhood aggression across raters, instruments, and age

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 $$\left| {r_g} \right|$$ r g : 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 $$\left| {r_g} \right|$$ r g : 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.

Continuity of Genetic Risk for Aggressive Behavior Across the Life-Course

“…We obtained effect sizes for the association between individual SNPs and aggression from the Ip et al ( 2021 ) GWAMA after omitting the target samples, i.e. analyses were run with no participants from the Netherlands for the Dutch target sample, and no participants from Australia for the Australian target sample (GWAMA sample size for the Netherlands: N SNPs = 7,722,825, N measures = 276,268, N individuals = 81,259, SNP-h 2 = 3.91%, SE = 0.42.…”

“…From this ‘polygenic’ genetic architecture, arises the need for very large GWAS sample sizes. Ip and colleagues ( 2021 ) conducted a genome wide meta-analysis (GWAMA) of aggression phenotypes in children and adolescents, aged 3 to 18 years. In a GWAMA, results from GWAS in multiple cohorts are combined with the aim to increase statistical power to find associations between a genetic marker (usually a single nucleotide polymorphism, i.e.…”

“…If phenotypes and genetic effects are comparable across cohorts from different ages and backgrounds, small effects of SNPs that do not attain significance in a single cohort may be genome wide significant in the GWAMA. In the Ip et al paper ( 2021 ), a total of 29 cohorts contributed 163 univariate GWAS to the early life aggression GWAMA. This resulted in a total of 328,935 observations from 87,485 unique individuals, aged 3 to 18 years.…”

“…The Ip et al ( 2021 ) aggression GWAMA is the largest childhood aggression GWAS to date, but no single genome-wide significant hits were observed. Despite this lack of single significant hits, Ip et al ( 2021 ) demonstrated that polygenic scores (PGSs), which sum the effects of a range of genetic markers, with markers included based on whether their p -value from the GWAS clears any of 16 thresholds between P = 1 and P < 1.0E-5, explained between 0.036 and 0.44% of the phenotypic variance in aggression in a hold-out sample of 7 year-old Dutch children ( N = 4491). In an Australian hold-out sample, childhood PGSs explained up to 0.2% of retrospectively assessed childhood conduct disorder.…”

“…In this study, we test the hypothesis that genetic risk factors, measured as DNA variants associated with increased aggressive behavior in early life (Ip et al 2021 ), increase the risk of aggression across the life-course. We quantified the contribution of a large number of variants by computing PGSs, and tested their association with aggression in two cohorts from two different countries, namely The Netherlands and Australia.…”