Genetic factors contribute to the development of alcohol dependence (AD). The only specific genes known to affect risk for AD are some of those coding enzymes important for ethanol metabolism. Promising linkage regions have been identified in two genome scans, but for genetically heterogeneous disorders like AD, strategies that rely purely on linkage for gene localization are not likely to result in gene identification. Linkage disequilibrium (LD) studies, using methods such as the transmission-disequilibrium test (TDT) of Spielman et al. (1993), provide a possible solution; these methods have the power to identify much shorter genomic regions likely to contain susceptibility loci than linkage methods, without being subject to population stratification error. Additionally, newly developed methods can greatly decrease risk of stratification error in case-control studies. LD studies (TDT and case-control) therefore are complementary to conventional linkage approaches. Specialized clinical materials must be collected, with rigorous ascertainment. We started a project collecting family trios with an alcohol-dependent proband in December 1996, and have now collected >150 predominantly European-American small nuclear families. We now propose to collect a sample of 360 additional small nuclear families, predominantly African-American, suitable for TDT analyses of AD, and a case-control sample of 1000 African-American (AA) subjects (500 ill and 500 well). The AA population, because it is recently admixed, is particularly advantageous for LD mapping, and LD has been demonstrated at great distances in AA populations. Families and unrelated subjects will be collected at Yale, Univ. CT, and MUSC, using the SSAGA as the primary diagnostic instrument. Additional phenotypic data will be collected using the FHAM and the NEO PI-R (personality). We will use both quantitative and categorical TDT analyses and make case-control comparisons with correction for admixture. Molecular studies will focus on genomic regions previously identified through linkage genome scans as being likely to contain susceptibility loci, plus positional candidate gene linkage disequilibrium and haplotype studies as the clinical sample is developed, with the goal of eventually using this sample for a whole-genome LD scan in a future study. New polymorphisms will be identified in candidate regions. Collection of a sample such as the one proposed here is a necessary step towards identifying specific genes that predispose for AD. Loci identified will be expected to have particular relevance for the AA community.
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