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
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Bi, Jinbo; Gelernter, Joel; Sun, Jiangwen et al. (2014) Comparing the utility of homogeneous subtypes of cocaine use and related behaviors with DSM-IV cocaine dependence as traits for genetic association analysis. Am J Med Genet B Neuropsychiatr Genet 165B:148-56
Sartor, Carolyn E; Kranzler, Henry R; Gelernter, Joel (2014) Rate of progression from first use to dependence on cocaine or opioids: a cross-substance examination of associated demographic, psychiatric, and childhood risk factors. Addict Behav 39:473-9
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Sun, Jiangwen; Bi, Jinbo; Kranzler, Henry R (2014) Multiview comodeling to improve subtyping and genetic association of complex diseases. IEEE J Biomed Health Inform 18:548-54
Xie, Pingxing; Kranzler, Henry R; Krystal, John H et al. (2014) Deep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence. Addict Biol 19:955-64
Gelernter, Joel (2014) SLC6A4 polymorphism, population genetics, and psychiatric traits. Hum Genet 133:459-61
Kos, Mark Z; Glahn, David C; Carless, Melanie A et al. (2014) Novel QTL at chromosome 6p22 for alcohol consumption: Implications for the genetic liability of alcohol use disorders. Am J Med Genet B Neuropsychiatr Genet 165B:294-302
Yang, Can; Li, Cong; Kranzler, Henry R et al. (2014) Exploring the genetic architecture of alcohol dependence in African-Americans via analysis of a genomewide set of common variants. Hum Genet 133:617-24
Sun, Jiangwen; Bi, Jinbo; Kranzler, Henry R (2014) Multi-view singular value decomposition for disease subtyping and genetic associations. BMC Genet 15:73

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