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

描述（申请人提供）：本研究的广泛、长期目标包括：（1）鉴定ADH基因簇和ALDH 2基因上的酒精依赖风险等位基因;（2）使用一组遗传标记对酒精依赖的诊断进行数学预测;（3）在蛋白质水平上为酒精依赖发展的神经生物学研究建立遗传基础;（4）为开发新的治疗酒依赖的药物提供了基础。具体目标包括：（1）检测ADH、ALDH 2基因与酒精依赖的关联性，并对各风险基因内的酒精依赖风险位点进行精细定位;（2）检测ADH、ALDH 2基因与三种酒精依赖共病的关联性，并对这些共病的风险位点进行精细定位，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绘制EA和AA中的风险位点，以了解任何预期关联和风险位点的人群特异性。该研究有望揭示ADH基因簇、ALDH 2基因与酒精依赖的真实关系，并对这些基因上的酒精依赖风险位点进行精细定位。这一发现将有助于更好地了解酒依赖的病因学、早期预测和预防酒依赖、开发诊断酒依赖的生物学标志物以及发现治疗酒依赖的新药。申请人提出了基于群体的研究来测试基因与疾病之间的关联，基因组对照研究来控制群体分层和混合效应（使用结构化关联方法和回归方法），表型对照研究来测试任何预期关联的表型特异性，以及群体对照研究来测试关联的群体特异性。最后，提出了一个以家庭为基础的研究，以确认从人口为基础的研究结果。将在总共2664名受试者中对这些基因中的240个标记进行基因分型（在初步研究中已经研究了27个标记，其中许多标记与酒精依赖呈正相关）。总之，本研究将确定一些酒精依赖的危险基因，帮助我们更好地了解酒精依赖的病因，并为新的药物提供潜在的靶点。

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.