Examining the role of common genetic variants on alcohol, tobacco, cannabis and illicit drug dependence: Genetics of vulnerability to drug dependence

• Type of Material: Article
• Authors: Rohan H. Palmer, Emory University; Leslie Brick, Emory University; NR Nugent, Rhode Island Hospital; LC Bidwell, Rhode Island Hospital; JE Mcgeary, Rhode Island Hospital; VS Knopik, Rhode Island Hospital; MC Keller, University of Colorado at Boulder
• Language: English
• Date: 2015-01-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Society for the Study of Addiction.
• Final Published Version (URL): http://dx.doi.org/10.1111/add.12815
• Title of Journal or Parent Work: Addiction
• ISSN: 0965-2140
• Volume: 110
• Issue: 3
• Start Page: 530
• End Page: 537
• Grant/Funding Information: Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438); the National Institute on Alcohol Abuse and Alcoholism; the National Institute on Drug Abuse; and the NIH contract “High throughput genotyping for studying the gene tic contributions to human disease’ (HHSN268200782096C).; Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446).; Funding for this study was provided by AA021113 (Palmer); DA023134 (Knopik); DA033302 (Bidwell); MH087240 (Nugent); MH100141 (Keller).; SAGE is one of the genome-wide as association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI.; Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01HG004422).; Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401); the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392); and the Family Study of Cocaine Dependence (FSCD; R01 DA013423).; Assistance with data cleaning was provided by the National Center for Biotechnology Information.
• Keywords: genome-wide association studies (GWAS); Tobacco Use Disorder; Marijuana Abuse; Alcoholism; Genotype; genetics; Genetic Variation; Cocaine-Related Disorders; Prevalence; Humans; United States; Polymorphism, Single Nucleotide; Phenotype; Comorbidity; genome-wide complex trait analysis; dependence vulnerability; Substance-Related Disorders; Genetic Predisposition to Disease; drug dependence; Addiction; Principal Component Analysis
• Research Categories: Biology, Genetics; Health Sciences, Mental Health; Health Sciences, Toxicology

Abstract

Background and Aims: Twin and family studies suggest that genetic influences are shared across substances of abuse. However, despite evidence of heritability, genome-wide association and candidate gene studies have indicated numerous markers of limited effects, suggesting that much of the heritability remains missing. We estimated (1) the aggregate effect of common single nucleotide polymorphisms (SNPs) on multiple indicators of comorbid drug problems that are typically employed across community and population-based samples, and (2) the genetic covariance across these measures. Participants: A total of 2596 unrelated subjects from the Study of Addiction: Genetics and Environment provided information on alcohol, tobacco, cocaine, cannabis and other illicit substance dependence. Phenotypic measures included: (1) a factor score based on DSM-IV drug dependence diagnoses (DD), (2) a factor score based on problem use (PU; i.e. 1+ DSM-IV symptoms) and (3) dependence vulnerability (DV; a ratio of DSM-IV symptoms to the number of substances used). Findings: Univariate and bivariate genome-wide complex trait analyses of this selected sample indicated that common SNPs explained 25-36% of the variance across measures, with DD and DV having the largest effects [h2SNP (standard error)=0.36 (0.13) and 0.33 (0.13), respectively; PU=0.25 (0.13)]. Genetic effects were shared across the three phenotypic measures of comorbid drug problems [rDD-PU=0.92 (0.08), rDD-DV=0.97 (0.08) and rPU-DV=0.96 (0.07)]. Conclusion: At least 20% of the variance in the generalized vulnerability to substance dependence is attributable to common single nucleotide polymorphisms. The additive effect of common single nucleotide polymorphisms is shared across important indicators of comorbid drug problems.