Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction.

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates.

up to 53,293 European ancestry Attention-deficit/hyperactivity disorder individuals, up to 164,684 European ancestry problematic alcohol use individuals, up to 186,875 European ancestry lifetime cannabis use individuals, up to 357,187 European ancestry individuals measuring reverse-coded age at first sexual intercourse, up to 336,121 European ancestry individuals measuring number of sexual partners, up to 426,379 European ancestry individuals measuring general risk tolerance, up to 1,251,809 European ancestry individuals measuring lifetime smoking initiation