Genetic and Biological Pathways Underlying the Relations between Executive Functioning and Externalizing Behaviors

Background: Across phenotypic and genotypic studies, executive functioning (EF) has been shown to be associated with externalizing behaviors, including attention-deficit/hyperactivity disorder (ADHD), aggression, and substance use, and is a proposed underlying mechanism of these behaviors. However, there is limited research on the shared biological mechanisms underpinning EF and externalizing behaviors, including their overlap at the level of genomic regions. Methods: The current study used genome-wide association study summary statistics of EF, ADHD, aggressive behavior, alcohol use, and alcohol use disorder to examine whether the heritability of these traits or the co-heritability between them is enriched for genes expressed in particular tissues or stratified by other annotation types. Additionally, the study examined the genomic regions contributing to the covariation between EF and the externalizing traits to identify genetic variants and genes that may be underlying their overlap. Results: First, across all phenotypes, there was evidence for enrichment of genetic signals in DNase hypersensitive sites and H3K4me1 regions, and significant enrichment among genes expressed in the anterior cingulate cortex and frontal cortex. Second, when combining results across regional methods, there was evidence for associations between EF and each of the externalizing behaviors in regions on chromosomes 1, 11, and 15. Conclusions: These findings highlight biological pathways that may link the relations between EF and externalizing behaviors and provides additional evidence of EF as an underlying mechanism of externalizing behavior.