This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The only specific genes known to affect risk for alcohol dependence (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 in the absence of disequilibrium for gene localization are likely to be insufficient for gene discovery. Linkage disequilibrium (LD) studies, using methods such as the transmission-disequilibrium test (TDT) (Spielman et al., 1993), provide a possible solution, and delineation of the properties of these methods has been the subject of many recent studies. These methods address the gene localization shortcomings of linkage designs. LD studies are complementary to conventional linkage approaches, but to be applied, they require specialized clinical materials, collected under rigorous ascertainment conditions. Our proposed sample will be recruited through affected probands and not conditioned on affection of more than one family member (although making use of multiple affecteds when available), and will be more representative of alcoholism in the target population than samples recruited based on multiple affecteds in each family. We will increase our chance of success by applying a novel approach to sample collection: we will specifically target the African-American (AA) population, a recently admixed population. Extensive regions of LD in AA populations have been demonstrated by Lautenberger et al. (2000); our data support LD to >7 cM in AAs recruited in Connecticut. While most project resources will be allocated to sample collection, we will also study a series of markers mapped to regions showing statistically significant linkage to AD in prior studies, and we will seek new markers in these regions and candidate loci.
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