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Genetic correlation, pleiotropy, and causal associations between substance use and psychiatric disorder

Published online by Cambridge University Press:  07 August 2020

Seon-Kyeong Jang
Department of Psychology, University of Minnesota, Minneapolis, MN, USA
Gretchen Saunders
Department of Psychology, University of Minnesota, Minneapolis, MN, USA
MengZhen Liu
Department of Psychology, University of Minnesota, Minneapolis, MN, USA
Yu Jiang
Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA
Dajiang J. Liu
Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA
Scott Vrieze*
Department of Psychology, University of Minnesota, Minneapolis, MN, USA
Author for correspondence: Scott Vrieze, E-mail:



Substance use occurs at a high rate in persons with a psychiatric disorder. Genetically informative studies have the potential to elucidate the etiology of these phenomena. Recent developments in genome-wide association studies (GWAS) allow new avenues of investigation.


Using results of GWAS meta-analyses, we performed a factor analysis of the genetic correlation structure, a genome-wide search of shared loci, and causally informative tests for six substance use phenotypes (four smoking, one alcohol, and one cannabis use) and five psychiatric disorders (ADHD, anorexia, depression, bipolar disorder, and schizophrenia).


Two correlated externalizing and internalizing/psychosis factor were found, although model fit was beneath conventional standards. Of 458 loci reported in previous univariate GWAS of substance use and psychiatric disorders, about 50% (230 loci) were pleiotropic with additional 111 pleiotropic loci not reported from past GWAS. Of the 341 pleiotropic loci, 152 were associated with both substance use and psychiatric disorders, implicating neurodevelopment, cell morphogenesis, biological adhesion pathways, and enrichment in 13 different brain tissues. Seventy-five and 114 pleiotropic loci were specific to either psychiatric disorders or substance use phenotypes, implicating neuronal signaling pathway and clathrin-binding functions/structures, respectively. No consistent evidence for phenotypic causation was found across different Mendelian randomization methods.


Genetic etiology of substance use and psychiatric disorders is highly pleiotropic and involves shared neurodevelopmental path, neurotransmission, and intracellular trafficking. In aggregate, the patterns are not consistent with vertical pleiotropy, more likely reflecting horizontal pleiotropy or more complex forms of phenotypic causation.

Original Article
Copyright © The Author(s) 2020. Published by Cambridge University Press

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