Deep sequencing of genes in ethanol-metabolism pathway in alcoholism

说明书(申请人提供)：“酒精中毒中乙醇代谢途径基因的深度测序”酒精脱氢酶(ADHS)和乙醛脱氢酶(ALDHs)是最有希望的途径之一，参与乙醇的代谢，从而导致酒精中毒的风险。本研究的具体目的包括：1.在7个ADH基因和1个ALDH基因中“穷尽”寻找变异，包括新的变异和罕见的变异，特别是潜在的功能变异，并建立这些基因变异的完整的生物信息学图谱。2.(主要目标)检验遗传变异(特别是可复制的和功能性的SNV，以及罕见的变异)与酒精依赖的关系，通过cis-eQTL分析确定风险变异的功能，然后确定因果变异。我们未来的长期目标是识别更多的因果基因座，然后利用多种研究策略确定这些基因座的功能。最终，这些功能基因座将成为治疗AD的新靶点。为了实现这两个具体目标，我们在研究设计中提出了两个步骤。第一步(目标1)是测序步骤：我们将对欧洲裔美国人和非洲裔美国人病例对照样本中的7个ADH基因和1个ALDH基因进行测序。步骤2(目标2)是关联测试步骤：我们将使用序列数据在上述两个样本(步骤1)中进行关联测试，以筛选它们与酒精中毒的潜在关联。然后，在测试步骤中，将选择在筛选步骤中确定的最有希望的酒精中毒变体，对其进行基因分型，并在两个更大的独立样本中测试它们与酒精中毒的关联。这个拟议的项目有许多创新之处。它最大的意义在于，在这些基因上识别酒精中毒的致病基因是非常有希望的。这些结果可能会对了解ADH和ALDH基因在酒精中毒中的作用产生重大影响，有助于我们更好地理解酒精中毒的发生机制。本研究结果也将有助于酒精中毒的早期预测和预防，开发酒精中毒诊断的生物标志物，以及改善酒精中毒的治疗。最后，预期的发现将有利于公众健康。

DESCRIPTION (provided by applicant): " Deep sequencing of genes in ethanol-metabolism pathway in alcoholism " Alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) are in one of the most promising pathways being involved in the metabolism of ethanol and thus in the risk for alcoholism. The specific aims of the proposed study include: 1. To "exhaustively" search for variants in 7 ADH genes and 1 ALDH gene, including novel variants and rare variants, especially the potential functional variants, and then to make a complete bioinformatic map of variants of these genes. 2. (Main goal) To test associations between genetic variants (especially the replicable and functional SNVs, and rare variants) and alcohol dependence, confirm the functions of risk variants by cis-eQTL analysis, and then to determine the causal variants. Our long-term objectives in the future are to identify more causal loci and then confirm the functions of these loci using multiple research strategies. Eventually, these functional loci will serve as the targets for novel treatments on AD. We propose two steps in the research design to achieve these two specific aims. Step 1 (Aim 1) is a sequencing step: we will sequence 7 ADH genes and 1 ALDH gene in a European American and an African American case-control samples. Step 2 (Aim 2) is an association testing step: we will perform association tests in the above two samples (Step 1) using sequence data, to screen the variants for their potential associations with alcoholism. Then, in the testing step, the most promising variants for alcoholism identified in the screening step will be selected, genotyped and tested for their associations with alcoholism in two larger independent samples. This proposed project has a number of innovations. Its greatest significance is that it is very promising to identify the causa loci for alcoholism at these genes. Results are likely to have a significant impact on the understanding of the roles of ADH and ALDH genes in alcoholism, helping us to better understand the mechanism of the development of alcoholism. The findings will also be very helpful for the early- life prediction and prevention for alcoholism, for the development of biological markers for diagnosis of alcoholism, and for the improvement of the treatment for alcoholism. Finally, the expected findings will benefit public health.