GABRA2

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 酒精依赖是一种非常普遍的疾病，与严重的发病率和死亡率有关。酒精依赖有一个重要的可遗传成分，估计占风险的50%-60%。我们最近使用了康涅狄格州258名白人酒精依赖者和335名筛选的对照组的样本来证实酒精依赖与GABRA2基因的关联，GABRA2基因于2003年在酒精中毒研究学会的一篇摘要中报道。我们发现，在酒精依赖受试者中，GABRA2基因3‘-一半的7个标记单倍型的额外频率为7%(44%比37%)，该单倍型的长度超过98000个核苷酸。 我们现在建议通过检查在Project Match(多中心酒精中毒治疗试验)中收集的1100名酒精受试者的更多样化的多中心样本与1100名对照受试者的集合来扩大我们对GABRA2基因和酒精中毒的病例对照关联调查。我们将使用这个样本以几种方式扩展我们的观察：i)在更大和更地理多样化的样本中测试关联，ii)使用额外的标记来更好地定义关联的3‘-终点，iii)潜在地通过使用更大和更遗传多样性的样本来关注关联区域III)检查与酒精依赖表型和共病条件的亚型的关联。我们将使用Duffy抗原作为纽约癌症项目匹配样本和对照样本中高加索人和黑人混合染色体的差异的初始筛查。如果检测到显著的差异，我们将计划与耶鲁大学的乔尔·格伦特博士合作，他的实验室已经开发出使用一组种族信息标记的技术，以实现统计校正病例对照遗传关联。 第二个目标将是检查人类GABRA2载体脱氧核糖核酸(CDNA)克隆与已知外显子4同义单核苷酸多态(SNP)的剪接或编码序列变化，该外显子在我们的初始样本中在酗酒者中出现频率较高。

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. Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. Alcohol dependence has a significant heritable component estimated to account for 50-60% of risk. We have recently used a Connecticut sample of 258 Caucasian alcohol dependent and 335 screened controls to confirm an association of alcohol dependence with the GABRA2 gene reported in an abstract at the Research Society on Alcoholism in 2003. We found a 7% excess frequency (44% vs. 37%) of a seven-marker haplotype extending 98,000 bp over the 3'-half of the GABRA2 gene for subjects with alcohol dependence. We are now proposing to extend our case control association investigations of the GABRA2 gene and alcoholism by examining a more diverse multi-center sample of 1100 alcoholic subjects collected in project MATCH (a multi-center alcoholism treatment trial) with a collection of 1100 control subjects. We will use this sample to extend our observations in several ways: i) to test for the association in a larger and more geographically diverse sample, ii) to use additional markers to better define the 3'-endpoint of association, iii) potentially focus the area of association by use of a larger and more genetically diverse sample iii) to examine for association with subtypes of alcohol dependent phenotype and co-morbid conditions. We will use the Duffy antigen as an initial screen for differences in Caucasian versus Black chromosome admixture in the MATCH versus control sample from the NYC Cancer Project. If significant differences are detected we will plan to collaborate with Dr. Joel Gelernter at Yale whose laboratory has developed techniques using a panel of racially informative markers to allow statistical correction case-control genetic associations. A second aim will be to examine human GABRA2 Carrier Deoxyribonucleic Acid (cDNA) clones for splice or coding sequence changes in linkage with a known exon 4 synonomous Single nucleotide polymorphism (SNP) present at higher frequency in alcoholics in our initial sample.