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基因的深度测序” 酒精脱氢酶（ADH）和乙醛脱氢酶（ALDH）是参与乙醇代谢的最有前途的途径之一，因此存在酒精中毒的风险。该研究的具体目标包括：1.“详尽”地寻找7个ADH基因和1个ALDH基因的变异体，包括新变异体和罕见变异体，特别是潜在的功能变异体，然后绘制这些基因变异体的完整生物信息学图谱。 2.（主要目标）测试遗传变异（尤其是可复制的、功能性的SNV和罕见变异）与酒精依赖之间的关联，通过cis-eQTL分析确认风险变异的功能，进而确定因果变异。我们未来的长期目标是识别更多的因果位点，然后使用多种研究策略确认这些位点的功能。最终，这些功能位点将成为 AD 新型治疗的靶点。我们提出研究设计的两个步骤来实现这两个具体目标。第 1 步（目标 1）是测序步骤：我们将对一名欧洲裔美国人和一名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对上述两个样本（步骤1）进行关联测试，以筛选变异体与酗酒的潜在关联。然后，在测试步骤中，将选择筛选步骤中确定的最有希望的酗酒变异，进行基因分型，并在两个较大的独立样本中测试它们与酗酒的关联。这个提议的项目有许多创新。其最大的意义在于，很有希望在这些基因上识别酗酒的致病位点。结果很可能对理解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。这些发现对于酒精中毒的早期预测和预防、酒精中毒诊断生物标志物的开发以及酒精中毒治疗的改进也将非常有帮助。最后，预期的结果将有利于公众健康。