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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011330-13
Application #
8434888
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Parsian, Abbas
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
13
Fiscal Year
2013
Total Cost
$529,341
Indirect Cost
$92,824
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Polimanti, Renato; Wang, Qian; Meda, Shashwath A et al. (2016) The Interplay Between Risky Sexual Behaviors and Alcohol Dependence: Genome-Wide Association and Neuroimaging Support for LHPP as a Risk Gene. Neuropsychopharmacology :
Schwantes-An, Tae-Hwi; Zhang, Juan; Chen, Li-Shiun et al. (2016) Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts. Behav Genet 46:151-69
Hart, Amy B; Lynch, Kevin G; Farrer, Lindsay et al. (2016) Which alcohol use disorder criteria contribute to the association of ADH1B with alcohol dependence? Addict Biol 21:924-38
Clarke, Toni-Kim; Smith, Andrew H; Gelernter, Joel et al. (2016) Polygenic risk for alcohol dependence associates with alcohol consumption, cognitive function and social deprivation in a population-based cohort. Addict Biol 21:469-80
Sherva, Richard; Wang, Qian; Kranzler, Henry et al. (2016) Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks. JAMA Psychiatry 73:472-80
Li, Gengxin (2016) A new model calling procedure for Illumina BeadArray data. BMC Genet 17:90
Wang, Qian; Polimanti, Renato; Kranzler, Henry R et al. (2016) Genetic factor common to schizophrenia and HIV infection is associated with risky sexual behavior: antagonistic vs. synergistic pleiotropic SNPs enriched for distinctly different biological functions. Hum Genet :
Nelson, E C; Agrawal, A; Heath, A C et al. (2016) Evidence of CNIH3 involvement in opioid dependence. Mol Psychiatry 21:608-14
Shmulewitz, Dvora; Meyers, Jacquelyn L; Wall, Melanie M et al. (2016) CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving. J Stud Alcohol Drugs 77:227-37
Polimanti, Renato; Kranzler, Henry R; Gelernter, Joel (2016) Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women. Neuropsychopharmacology 41:2688-96

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