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

Nat Neurosci. 2021 Oct;24(10):1367-1376. doi: 10.1038/s41593-021-00908-3. Epub 2021 Aug 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Attention Deficit Disorder with Hyperactivity / genetics
  • Behavior, Addictive / genetics*
  • Behavior, Addictive / psychology
  • Behavioral Symptoms / genetics
  • Behavioral Symptoms / psychology
  • Computational Biology
  • Crime / psychology
  • Genetic Association Studies*
  • Genome-Wide Association Study
  • HIV Infections / genetics
  • HIV Infections / psychology
  • Humans
  • Meta-Analysis as Topic
  • Multifactorial Inheritance
  • Multivariate Analysis
  • Opioid-Related Disorders / genetics
  • Opioid-Related Disorders / psychology
  • Reproducibility of Results
  • Self-Control*
  • Suicide
  • Unemployment