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

Seon Kyeong Jang, Gretchen Saunders, Mengzhen Liu, Yu Jiang, Dajiang J. Liu, Scott Vrieze

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41 Scopus citations


Background 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. Method 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). Results 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. Conclusions 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 languageEnglish (US)
Pages (from-to)968-978
Number of pages11
JournalPsychological medicine
Issue number5
Early online dateAug 7 2020
StatePublished - Apr 7 2022

Bibliographical note

Publisher Copyright:
Copyright © The Author(s) 2020. Published by Cambridge University Press.


  • Addiction
  • GWAS
  • Mendelian randomization
  • comorbidity
  • pleiotropy
  • psychopathology


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