" Deep sequencing of genes in ethanol-metabolism pathway in alcoholism " Alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) are in one of the most promising pathways being involved in the metabolism of ethanol and thus in the risk for alcoholism.
The specific aims of the proposed study include: 1. To "exhaustively" search for variants in 7 ADH genes and 1 ALDH gene, including novel variants and rare variants, especially the potential functional variants, and then to make a complete bioinformatic map of variants of these genes. 2. (Main goal) To test associations between genetic variants (especially the replicable and functional SNVs, and rare variants) and alcohol dependence, confirm the functions of risk variants by cis-eQTL analysis, and then to determine the causal variants. Our long-term objectives in the future are to identify more causal loci and then confirm the functions of these loci using multiple research strategies. Eventually, these functional loci will serve as the targets for novel treatments on AD. We propose two steps in the research design to achieve these two specific aims. Step 1 (Aim 1) is a sequencing step: we will sequence 7 ADH genes and 1 ALDH gene in a European American and an African American case-control samples. Step 2 (Aim 2) is an association testing step: we will perform association tests in the above two samples (Step 1) using sequence data, to screen the variants for their potential associations with alcoholism. Then, in the testing step, the most promising variants for alcoholism identified in the screening step will be selected, genotyped and tested for their associations with alcoholism in two larger independent samples. This proposed project has a number of innovations. Its greatest significance is that it is very promising to identify the causa loci for alcoholism at these genes. Results are likely to have a significant impact on the understanding of the roles of ADH and ALDH genes in alcoholism, helping us to better understand the mechanism of the development of alcoholism. The findings will also be very helpful for the early- life prediction and prevention for alcoholism, for the development of biological markers for diagnosis of alcoholism, and for the improvement of the treatment for alcoholism. Finally, the expected findings will benefit public health.

Public Health Relevance

to public health This proposed project will search for causal loci for alcohol dependence, which will help us better understand the biological basis of this phenotype. The expected findings will significantly contribute to the improvement of public health.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA021380-01A1
Application #
8637543
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Murray, Gary
Project Start
2014-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$188,169
Indirect Cost
$44,419
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zuo, Lingjun; Wang, Kesheng; Luo, Xingguang (2014) Use of diplotypes - matched haplotype pairs from homologous chromosomes - in gene-disease association studies. Shanghai Arch Psychiatry 26:165-70
Zuo, Lingjun; Lu, Lingeng; Tan, Yunlong et al. (2014) Genome-wide association discoveries of alcohol dependence. Am J Addict 23:526-39
Zuo, Lingjun; Wang, Kesheng; Wang, Guilin et al. (2014) Common PTP4A1-PHF3-EYS variants are specific for alcohol dependence. Am J Addict 23:411-4
Pan, Yue; Luo, Xingguang; Liu, Xuefeng et al. (2013) Genome-wide association studies of maximum number of drinks. J Psychiatr Res 47:1717-24