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”酒精脱氢酶（ADHS）和醛脱氢酶（ALDHS）是参与乙醇的最有希望的途径之一酗酒的风险。拟议研究的具体目的包括：1。“详尽”搜索7种ADH基因和1个ALDH基因的变体，包括新型变体和稀有变体，尤其是潜在的功能变体，然后制作完整的生物信息图。这些基因。 2。（主要目标）测试遗传变异（尤其是可复制和功能性SNV，稀有变体）和酒精依赖性之间的关联，通过顺式EQTL分析确认风险变体的功能，然后确定因果变体。我们将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确认这些基因座的功能。最终，这些功能基因座将成为AD新型治疗方法的靶标。我们在研究设计中提出了两个步骤，以实现这两个特定目标。步骤1（AIM 1）是一个测序步骤：我们将在欧美和非裔美国人病例对照样本中对7 ADH基因和1个ALDH基因进行序列。步骤2（AIM 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，以筛选其与酒精中毒的潜在关联的变体。然后，在测试步骤中，将在两个较大的独立样本中选择，基因分型和测试其与酒精中毒的关联。这个拟议的项目有许多创新。它最大的意义是，在这些基因上识别酒精中毒的CAUSA基因座非常有前途。结果可能会对对ADH和ALDH基因在酒精中毒的作用的理解产生重大影响，从而帮助我们更好地了解酒精中毒的发展机制。这些发现也将对酒精中毒的早期生活预测和预防，开发用于酒精中毒的生物学标志物以及改善酒精中毒治疗的生物标志物也非常有帮助。最后，预期的发现将使公共卫生受益。