A Family-Based Genome Wide Association Study of Externalizing Behaviors

Abstract

Shared genetic factors contribute to the high degree of comorbidity among externalizing problems (e.g. substance use and antisocial behavior). We leverage this common genetic etiology to identify genetic influences externalizing problems in participants from the Collaborative Study on the Genetics of Alcoholism (European ancestry = 7568; African ancestry = 3274). We performed a family-based genome-wide association study (GWAS) on externalizing scores derived from criterion counts of five DSM disorders (alcohol dependence, alcohol abuse, illicit drug dependence, illicit drug abuse, and either antisocial personality disorder or conduct disorder). We meta analyzed these results with a similar measure of externalizing in an independent sample, Spit for Science (combined sample N = 15,112). We did not discover any robust genome-wide significant signals. Polygenic scores derived from the ancestry-specific GWAS summary statistics predicted externalizing problems in an independent European ancestry sample, but not in those of African ancestry. However, these PRS were no longer significant after adjusting for multiple testing. Larger samples with deep phenotyping are necessary for the discovery of SNPs related to externalizing problems.

Keywords: Externalizing; GWAS; Polygenic Scores; Substance use.

Figure 1.

Manhattan plots for inverse-variance weighted meta analysis of ancestry specific GWAS results. The y axis represents – log(P values) for association of variants with externalizing problem scores in each ancestry group (European Ancestry N = 7568; African Ancestry N = 3274). The dotted horizontal line represents the threshold for genome-wide significance (p < 5 × 10⁻⁸).

Figure 2.

Manhattan plot for meta-analytic results from gene-based analyses (inverse variance fixed effects meta-analysis). The y axis represents – log(P values) for association of variants with externalizing problem scores. The dotted horizontal line represents the threshold for genome-wide significance (p < 2.78 × 10⁻⁶).