This is a third submission of an R21 proposal to study alcohol dependence genetics in a large pedigree in China. Alcohol dependence (AD) is a complex genetic trait. For complex genetic traits such as alcohol dependence, genes can be located via linkage analysis. Linkage mapping for complex traits can be facilitated through (a) increasing homogeneity of genetic background, (b) increasing homogeneity of environmental exposure, and (c) increasing pedigree size. We have identified a Han Chinese population including several extended pedigrees in rural northern Hunan province (China) with a high rate of alcohol dependence and little exposure to other commonly-abused substances. The """"""""key investigators"""""""" on this project visited China in November 2004 and met with senior representatives of the extended pedigree and with local government officials, all of whom pledged support for a genetic study of alcohol dependence in this population. This set of pedigrees has about 10,000 members. Based on survey data, the (current) rate of alcohol dependence in this pedigree is about 10.4%; and in a subpedigree (4 large branches), where we propose to start our study, the (current) rate is 11.4%. Flushing in response to alcohol ingestion also segregates in this pedigree. For this pilot project, we propose to (1) recruit 600 individuals from four branches of the pedigree, and perform psychiatric evaluations with the Chinese version of the Diagnostic Interview for Genetics Studies (DIGS), already in use by our consultant Dr. Ming Tsuang; (2) isolate DNA from each subject in Dr. Hong-wen Deng's laboratory at Hunan Normal University (Changsha); (3) genotype 30 markers mapped to chromosome 4 in Dr. Deng's lab, and complete genetic linkage analysis for those markers and alcohol dependence trait; (4) and continue the process of obtaining Chinese government approval for export of DNA to Dr. Gelernter's laboratory for further genotyping. Chromosome 4 was chosen for initial work because it has been identified by several AD linkage studies, and two gene clusters previously associated to alcohol dependence (GABRA2 region, and an ADH cluster) map to this chromosome. This will lay the groundwork for a future R01 project with the goal of ascertaining more of the pedigree, with genomewide investigation. This study will improve understanding of the genes that influence risk for alcohol dependence, in Chinese populations, and in comparison with European-American populations. ? ? ?
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