Deep sequencing of genes in ethanol-metabolism pathway in alcoholism

酒精中毒乙醇代谢途径基因的深度测序

• 批准号: 8637543
• 负责人: XINGGUANG LUO
• 金额: $ 18.82万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637543
• 关键词: 4q21; Acetaldehyde; Acetates; Adoption; African American; Alcohol dehydrogenase; Alcohol dependence; Alcoholism; American; Base Pairing; Bioinformatics; Biological; Biological Markers; Biological Process; Candidate Disease Gene; Carbon Dioxide; Chromosomes, Human, Pair 4; Clinical; Clinical Trials; DNA Sequence; Data; Development; Diagnosis; Environmental Risk Factor; Ethanol; Ethanol Metabolism; European; Familial disease; Family; Funding; Future; Gene Cluster; Generations; Genes; Genetic; Genetic Variation; Genotype; Goals; Haplotypes; Health; Hereditary Disease; Human; Laboratory Study; Life; Liver; Maps; Mediating; Pathway interactions; Phase; Phenotype; Public Health; Reading; Research; Research Design; Risk; Role; Sampling; Step Tests; Technology; Testing; Time; Twin Multiple Birth; Variant; alcoholism prevention; alcoholism therapy; aldehyde dehydrogenase 1; aldehyde dehydrogenases; base; candidate marker; case control; deep sequencing; genetic variant; genome wide association study; genome-wide linkage; innovation; novel; rare variant; risk variant; screening; single molecule; success; tool

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.

描述（由申请人提供）：“酒精中毒中乙醇代谢途径中基因的深度测序“乙醇脱氢酶（ADH）和乙醛脱氢酶（ALDH）是参与乙醇代谢并因此参与酒精中毒风险的最有前途的途径之一。本研究的具体目标包括：1.对7个ADH基因和1个ALDH基因的变异进行“穷尽性”搜索，包括新变异和罕见变异，特别是潜在的功能变异，并构建这些基因变异的完整生物信息学图谱。2. (Main目的）检测遗传变异（特别是可复制和功能性SNV，以及罕见变异）与酒精依赖的关系，通过cis-eQTL分析确定风险变异的功能，进而确定致病变异。我们未来的长期目标是确定更多的因果基因座，然后使用多种研究策略来确认这些基因座的功能。最终，这些功能位点将成为AD新治疗的靶点。我们提出了两个步骤的研究设计，以实现这两个具体目标。第1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。第2步（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中进行关联测试（步骤1），以筛选变体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鉴定的最有希望的酒精中毒变体，进行基因分型，并在两个较大的独立样本中测试它们与酒精中毒的关联。这个项目有许多创新之处。其最大的意义在于，它是非常有希望的，以确定在这些基因上的酒精中毒的病因位点。研究结果可能对理解ADH和ALDH基因在酒精中毒中的作用产生重大影响，帮助我们更好地了解酒精中毒的发展机制。这一发现对于酒精中毒的早期预测和预防、酒精中毒诊断生物学标志物的开发以及酒精中毒治疗的改进也将是非常有帮助的。最后，预期的发现将有利于公共卫生。