Fine-mapping the risk loci for alcoholism in ADH gene cluster and ALDH2 gene

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DESCRIPTION (provided by applicant): 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 include: (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.