Abstract
BACKGROUND: Executive functioning (EF) has been proposed as a transdiagnostic risk factor for externalizing disorders and behavior more broadly, including attention-deficit/hyperactivity disorder (ADHD), aggression, and alcohol use. Previous research has demonstrated both phenotypic and genetic overlap among these behaviors, but has yet to examine EF as a common causal mechanism. The current study examined reciprocal causal associations between EF and several externalizing behaviors using a Mendelian randomization (MR) approach. METHODS: Two-sample MR was conducted to test causal associations between EF and externalizing behaviors. Summary statistics from several genome-wide association studies (GWASs) were used in these analyses, including GWASs of EF, ADHD diagnostic status, drinks per week, aggressive behavior, and alcohol use disorder (AUD) diagnostic status. Multiple estimation methods were employed to account for horizontal pleiotropy (e.g., inverse variance weighted, MR-PRESSO, MR-MIX). RESULTS: EF demonstrated significant causal relationships with ADHD (P < 0.01), AUD (P < 0.03), and alcohol consumption (P < 0.01) across several estimation methods. Reciprocally, ADHD showed a significant causal influence on EF (P < 0.03). Nonetheless, caution should be used when interpreting these findings as there was some evidence for horizontal pleiotropy in the effect of EF on ADHD and significant heterogeneity in variant effects in the other relations tested. There were no significant findings for aggression. CONCLUSIONS: Findings suggest that EF may be a causal mechanism underlying some externalizing behaviors, including ADHD and alcohol use, and that ADHD may also lead to lower performance on EF tasks.