Alcohol dependence (AD), of all genetically influenced traits, is one of the most costly to society, in the United States and worldwide. Genetic epidemiologic studies consistently report the heritability of AD to be ~0.50-0.60. Genomewide linkage studies from different research groups have only rarely reported linkage peaks that attain conventional statistical significance, but several such peaks have been replicated independently in numerous studies, supporting their probable validity;and candidate genes based on linkage results have in several cases been replicated strongly and consistently across different research groups (including ours). Although AD cuts across society, minority populations, and specifically African-Americans (AAs), are understudied. To address this issue, we started a project in 2002 (AA11330) of which one goal was the collection of a sample of AA alcohol-dependent cases and controls (for mapping by admixture linkage disequilibrium, and other gene mapping methods). We have now recruited a total of 1500 unrelated AA subjects, all of whom were assessed with the state-of-the-art SSADDA (Semi-Structured Assessment for Drug Dependence and Alcoholism), which includes considerable detail regarding AD beyond merely the diagnostic criteria. We will augment our SSADDA-assessed control sample with additional subjects from the NIMH Genetics Initiative, yielding a sample of 1500 AD cases and 1500 controls. Based on a smaller sample (1000/1000), we previously proposed a genomewide association study through CIDR, using the Illumina HumanHap650Y marker set, which was approved for genotyping with the contingency that an additional independent NIH-supported project be funded. That approval has been extended to accommodate the present amended proposal. This would be a pioneering WGAS in an AA AD population;we expect to obtain invaluable new insights into AD in the AA population, and into the structure of the AA population;and will also address associated phenotypes, including comorbid disorders (such as cocaine or opioid dependence). We propose replication of most-significant signals in additional AA and EA samples;and collection of an additional 1250 SSADDA-assessed affected subjects to permit a more powerful GWAS in YR05.

Public Health Relevance

Alcohol dependence is genetically influenced. The purpose of this project is to use a new and powerful technique, genomewide association analysis, to identify genes that influence risk for alcohol dependence in African-Americans, and to replicate key findings. 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 #
5R01AA017535-05
Application #
8527623
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Parsian, Abbas
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$532,608
Indirect Cost
$91,611
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Li, Dawei; Zhao, Hongyu; Kranzler, Henry R et al. (2015) Genome-wide association study of copy number variations (CNVs) with opioid dependence. Neuropsychopharmacology 40:1016-26
Levey, D F; Le-Niculescu, H; Frank, J et al. (2014) Genetic risk prediction and neurobiological understanding of alcoholism. Transl Psychiatry 4:e391
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
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
Gelernter, J; Sherva, R; Koesterer, R et al. (2014) Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene. Mol Psychiatry 19:717-23
Gelernter, Joel; Kranzler, Henry R; Sherva, Richard et al. (2014) Genome-wide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways. Biol Psychiatry 76:66-74
Gelernter, J; Kranzler, H R; Sherva, R et al. (2014) Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci. Mol Psychiatry 19:41-9
Jensen, Kevin P; Kranzler, Henry R; Stein, Murray B et al. (2014) The effects of a MAP2K5 microRNA target site SNP on risk for anxiety and depressive disorders. Am J Med Genet B Neuropsychiatr Genet 165B:175-83

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