Genetic factors contribute to the development of alcohol dependence (AD). Substantial progress has been made in identifying specific risk genes, but currently known well-supported loci still account for only a small proportion of the overall disease risk. In the last iteration of this project, we recruited and rigorously assessed ~2000 AD subjects and relatives, with oversampling of African Americans (AAs);we also contributed to the understanding of AD risk though candidate gene studies of AD and related phenotypes, and gene-by-environment interaction involving AD risk (with mapping by admixture linkage disequilibrium studies currently in progress). It is widely appreciated that whole genome association studies (WGAS) have the potential to reveal more risk loci. The quality of such studies is always limited by the quality of the available phenotypic assessments;our investment in state-of-the-art phenotypic characterization has resulted in a sample that should be an outstanding one to probe for novel risk loci by this method. In the present application, we propose to recruit an additional 1250 AD subjects (primarily AAs and EAs);and to conduct a WGAS study of 2000 European American AD subjects and 4000 controls in two waves of 1000 affecteds and 2000 controls;and follow-up studies of implicated loci (in an expanded sample of already-collected AD subjects and a large sample of German AD affecteds and controls) via SNP genotyping and deep sequencing. Additionally, we will study high resolution copy number variation (CNV) in a subsample of AD subjects. When both waves of the study have been completed, we will be able to study subphenotypes within the sample (e.g., family history positive vs. negative, AD with or without other substance dependence comorbidity), both in case-only comparisons and in comparison to control subjects. A companion WGAS application with already-collected AA samples has been contingently-approved by CIDR for genotyping. The current project could provide the opportunity for instructive comparison of risk loci between AA and EA populations, with the potential to isolate associated regions. This project has the potential to contribute substantially to our growing knowledge of genetic risk factors for AD and related traits.

Public Health Relevance

Alcohol dependence is genetically influenced. The main purpose of this project is to use a new and powerful technique, genomewide association analysis, to identify genes that influence risk for alcohol dependence. Successful completion of this research would be expected to increase our understanding of alcohol dependence, and potentially to lead to early identification of susceptible individuals, and to new treatments.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Parsian, Abbas
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Yale University
Schools of Medicine
New Haven
United States
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Smith, Andrew H; Ovesen, Peter L; Skeldal, Sune et al. (2018) Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2. Alcohol Clin Exp Res 42:2337-2348
Polimanti, R; Kaufman, J; Zhao, H et al. (2018) A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus. Mol Psychiatry 23:154-160
Polimanti, R; Kaufman, J; Zhao, H et al. (2018) Trauma exposure interacts with the genetic risk of bipolar disorder in alcohol misuse of US soldiers. Acta Psychiatr Scand 137:148-156
Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302
Polimanti, Renato; Gelernter, Joel (2018) ADH1B: From alcoholism, natural selection, and cancer to the human phenome. Am J Med Genet B Neuropsychiatr Genet 177:113-125
Zhou, Hang; Cheng, Zhongshan; Bass, Nicholas et al. (2018) Genome-wide association study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression. Transl Psychiatry 8:208
Montalvo-Ortiz, Janitza L; Zhou, Hang; D'Andrea, Ivana et al. (2018) Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response. Mol Psychiatry 23:2277-2286
Cheng, Zhongshan; Zhou, Hang; Sherva, Richard et al. (2018) Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans. Biol Psychiatry 84:762-770
Hancock, D B; Guo, Y; Reginsson, G W et al. (2018) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry 23:1-9
Cabana-Domínguez, Judit; Arenas, Concepció; Cormand, Bru et al. (2018) MiR-9, miR-153 and miR-124 are down-regulated by acute exposure to cocaine in a dopaminergic cell model and may contribute to cocaine dependence. Transl Psychiatry 8:173

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