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

Richard Karlsson Linnér ,Karin J H Verweij ,Paul A Slesinger ,Joel Gelernter ,Laura J Bierut ,Joëlle A Pasman ,Jessica E Salvatore ,K Paige Harden ,Gayathri Pandey ,Sandra Sanchez‐Roige ,Abraham A Palmer ,Scott Vrieze ,Ronald P Hart ,John I Nürnberger ,Andrew D Grotzinger ,Laura Almasy ,Emma C Johnson ,Dongbing Lai ,Abbas Parsian ,Lance O Bauer ,Danielle M Dick ,Jacquelyn L Meyer ,Allison Goate ,Jorim J Tielbeek ,Samuel Kuperman ,Kathleen Mullan Harris ,Bernice Porjesz ,Howard J Edenberg ,Sara Brin Rosenthal ,Marc A Schuckit ,Henry R Kranzler ,Xiaoling Xuei ,Vivia V Mccutcheon ,Michael J Chao ,David B Chorlian ,Andrew I Brooks ,Travis T Mallard ,Hemin Chin ,Ronald De Vlaming ,Ashwini K Pandey ,Holly E Poore ,Arpana Agrawal ,Morgan N Driver ,Jay A Tischfield ,Trey Ideker ,Irwin D Waldman ,Fazil Alıev ,Peter B Barr ,Andrey P Anokhin ,Tatiana Foroud ,John Kramer ,Victor Hesselbrock ,Grace Chan ,Scott F Saccone ,James W Madole ,Martin H Plawecki ,Manav Kapoor ,Sivan Kinreich ,Hang Zhou ,Kathleen K Bucholz ,Leah Wetherill ,Dajiang Liu ,Elliot M Tucker‐Drob ,Philipp Koellinger ,Yunlong Liu ,Denise M Scott ,Chella Kamarajan ,Mengzhen Liu ,Jian Zhang ,Sean O’connor ,Spencer Lourens ,Laura Ación ,Rachel L Kember ,John P Rice

doi:10.1038/s41593-021-00908-3

Abstract

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior, and ADHD, 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.

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