The broad, long-term objectives of this study include: (1) to identify the risk alleles for alcohol dependence at ADH gene cluster and ALDH2 gene; (2) to mathematically predict the diagnosis of alcohol dependence using a set of genetic markers; (3) to create a genetic basis for the neurobiological study on the development of alcohol dependence at a protein level; and (4) to provide a foundation to develop novel pharmacotherapeutic agents for the treatment of alcohol dependence.
The specific aims i nclude: (1) to test the associations between each ADH, ALDH2 gene and alcohol dependence, and then fine-map the risk sites for alcohol dependence within each risk gene; (2) to test the associations between each gene and three alcohol dependence comorbid disorders, and then fine-map the risk sites for these disorders, in order to know the phenotype-specificity of these risk genes; (3) to test the above associations and fine-map the risk sites in EAs and AAs, to understand the population-specificity of any expected association and risk site. This proposed study is promising to reveal the true relationships between ADH gene cluster, ALDH2 gene and alcohol dependence and to fine-map the alcohol dependence risk sites at these genes. The findings will be very helpful for better understanding the etiology of alcohol dependence, for the early-life prediction and prevention of alcohol dependence, for developing biological markers for diagnosis, and for discovering new drugs on treating alcohol dependence. The applicants propose a population-based study to test associations between genes and diseases, a genomic control study to control for population stratification and admixture effects (using a structured association method and a regression method), a phenotype control study to test the phenotype-specificity of any expected association, and a population control study to test the population-specificity of associations. Finally, a family-based study is proposed to confirm the results from population-based studies. 240 markers within these genes will be genotyped in a total of 2664 subjects (27 markers have been studied in the preliminary study and many of them are positively associated with alcohol dependence). In a word, this study will identify some risk genes for alcohol dependence, helping us better understand the etiology of alcohol dependence and provide potential targets for new drugs. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016015-02
Application #
7234761
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Ren, Zhaoxia
Project Start
2006-06-01
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$142,446
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wang, Kesheng; Liu, Ying; Ouedraogo, Youssoufou et al. (2018) Principal component analysis of early alcohol, drug and tobacco use with major depressive disorder in US adults. J Psychiatr Res 100:113-120
Zuo, Lingjun; Wang, Zhiren; Tan, Yunlong et al. (2016) piRNAs and Their Functions in the Brain. Int J Hum Genet 16:53-60
Cao, Yuping; Li, Longfei; Zhao, Xingfu et al. (2016) Effects of Exposure to Domestic Physical Violence on Children's Behavior: A Chinese Community-based Sample. J Child Adolesc Trauma 9:127-135
Zuo, Lingjun; Saba, Laura; Lin, Xiandong et al. (2015) Significant association between rare IPO11-HTR1A variants and attention deficit hyperactivity disorder in Caucasians. Am J Med Genet B Neuropsychiatr Genet 168:544-56
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
Wang, Kesheng; Luo, Xingguang; Zuo, Lingjun (2014) Genetic factors for alcohol dependence and schizophrenia: common and rare variants. Austin J Drug Abuse Addict 1:
Zuo, Lingjun; Wang, Kesheng; Zhang, Xiang-Yang et al. (2013) Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism. Hum Genet 132:735-43
Zuo, Lingjun; Wang, Kesheng; Zhang, Xiang-Yang et al. (2013) NKAIN1-SERINC2 is a functional, replicable and genome-wide significant risk gene region specific for alcohol dependence in subjects of European descent. Drug Alcohol Depend 129:254-64
Zuo, Lingjun; Wang, Ke-Sheng; Zhang, Xiang-Yang et al. (2013) Rare SERINC2 variants are specific for alcohol dependence in individuals of European descent. Pharmacogenet Genomics 23:395-402
Zuo, Lingjun; Zhang, Heping; Malison, Robert T et al. (2013) Rare ADH variant constellations are specific for alcohol dependence. Alcohol Alcohol 48:9-14

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