Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans |
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| Authors: | Leah Wetherill Dongbing Lai Emma C Johnson Andrey Anokhin Lance Bauer Kathleen K Bucholz Danielle M Dick Ahmad R Hariri Victor Hesselbrock Chella Kamarajan John Kramer Samuel Kuperman Jacquelyn L Meyers John I Nurnberger Jr Marc Schuckit Denise M Scott Robert E Taylor Jay Tischfield Bernice Porjesz Alison M Goate Howard J Edenberg Tatiana Foroud Ryan Bogdan Arpana Agrawal |
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| Institution: | 1. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University, Indianapolis, Indiana;2. Department of Psychiatry, Washington University School of Medicine, Washington University, Saint Louis, Missouri;3. Department of Psychiatry, University of Connecticut School of Medicine, University of Connecticut, Farmington, Connecticut;4. Department of Psychology & College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, Virginia;5. Department of Psychology, Duke Institute for Brain Sciences, Duke University, Durham, North Carolina;6. SUNY. Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, New York;7. Department of Psychiatry, University of Iowa Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa;8. Department of Psychiatry, Indiana University School of Medicine, Indiana University, Indianapolis, Indiana;9. Department of Psychiatry, University of California San Diego, San Diego, California;10. Departments of Pediatrics and Human Genetics, Howard University, Washington, District of Columbia;11. Department of Pharmacology, Howard University, Washington, District of Columbia;12. Department of Genetics, Rutgers University, Piscataway, New Jersey;13. Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, New York;14. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indiana University, Indianapolis, Indiana;15. Department of Psychological and Brain Sciences, Washington University in Saint Louis, Saint Louis, Missouri;16. Arpana Agrawal, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, CB 8134, Saint Louis, MO 63110.;17. Ryan Bogdan, BRAINLab, Department of Psychological and Brain Sciences, and Division of Biology and Biomedical Sciences, Washington University in St. Louis, Saint Louis, MO 63110. |
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| Abstract: | Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome‐wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European‐Americans (EA; 2927 cases) and 3132 African‐Americans (AA: 1315 cases) participating in the family‐based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome‐wide significant (GWS; P < 5E‐08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion‐deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans‐ancestral meta‐analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward‐related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non‐European samples with distinct patterns of substance use may lead to the identification of novel ancestry‐specific genetic markers of risk. |
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| Keywords: | African‐American alcohol dependence drug dependence European‐American fMRI genetics GWAS heritability neural reward ventral striatum |
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