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

描述(申请人提供)：这项研究的广泛和长期目标包括：(1)在ADH基因簇和ALDH2基因上确定酒精依赖的风险等位基因；(2)利用一套遗传标记从数学上预测酒精依赖的诊断；(3)从蛋白质水平为酒精依赖发生发展的神经生物学研究创造遗传学基础；以及(4)为开发治疗酒精依赖的新型药物治疗药物提供基础。具体目标包括：(1)检测每个ADH和ALDH2基因与酒精依赖之间的关联，然后精细定位每个风险基因内的酒精依赖风险位点；(2)测试每个基因与三个酒精依赖并存疾病的关联，然后精细定位这些疾病的风险位点，以了解这些风险基因的表型特异性；(3)测试上述关联并精细定位EAs和AAs中的风险位点，以了解任何预期的关联和风险位置的人群特异性。这项研究有望揭示ADH基因簇和ALDH2基因与酒精依赖之间的真实关系，并精细定位这些基因上的酒精依赖风险位置。这些发现将有助于更好地了解酒依赖的病因，对酒依赖的早期预测和预防，开发用于诊断的生物标志物，以及发现治疗酒依赖的新药将非常有帮助。申请人提出了一项基于群体的研究，以测试基因和疾病之间的关联，一项基因组对照研究，以控制种群分层和混合效应(使用结构化关联方法和回归方法)，一项表型对照研究，以测试任何预期关联的表型专一性，以及一项人口对照研究，以测试关联的种群专一性。最后，提出了一项以家庭为基础的研究，以证实基于人口的研究的结果。这些基因中的240个标记将在总共2664名受试者中进行基因分型(27个标记已经在初步研究中进行了研究，其中许多与酒精依赖呈正相关)。总之，本研究将确定一些酒依赖的危险基因，帮助我们更好地了解酒依赖的病因，并为新药提供潜在的靶点。

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.