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

精细定位ADH基因簇和ALDH2基因中酗酒的风险位点

• 批准号: 7430484
• 负责人: XINGGUANG LUO
• 金额: $ 14.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7430484
• 关键词: Accounting; Admixture; Affect; African American; Alcohol dependence; Alcoholism; All Sites; Alleles; American; Anxiety Disorders; Asian Americans; Biological Markers; Controlled Study; Dependence; Development; Diagnosis; Disease; Disease regression; Disorder by Site; Drug Addiction; Enzymes; Equilibrium; Ethnic Origin; Etiology; European; Family; Foundations; Future; Gene Cluster; Genes; Genetic; Genetic Markers; Genetic Structures; Genomics; Genotype; Goals; Haplotypes; Life; Light; Maps; Measures; Methods; Mood Disorders; Neurobiology; Pharmaceutical Preparations; Phase; Phenotype; Population; Population Control; Prevention; Proteins; Reporting; Research; Research Personnel; Risk; Sample Size; Site; Specificity; Stratification; Structure; Testing; Time; Variant; aldehyde dehydrogenases; base; drug discovery; gene interaction; innovation; novel; programs; trend

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.

描述（由申请人提供）：本研究的广泛、长期目标包括：（1）确定ADH基因簇和ALDH2基因中酒精依赖的风险等位基因； (2) 使用一组遗传标记以数学方式预测酒精依赖的诊断； (3) 为蛋白质水平上酒精依赖发展的神经生物学研究奠定遗传基础； (4)为开发用于治疗酒精依赖的新型药物治疗剂提供基础。具体目标包括：（1）测试每个ADH、ALDH2基因与酒精依赖之间的关联，然后精细绘制每个风险基因内酒精依赖的风险位点； （2）测试每个基因与三种酒精依赖共存疾病之间的关联，然后精细绘制这些疾病的风险位点，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。这项拟议的研究有望揭示 ADH 基因簇、ALDH2 基因和酒精依赖之间的真正关系，并精细绘制这些基因的酒精依赖风险位点。这些发现对于更好地了解酒精依赖的病因、早期预测和预防酒精依赖、开发用于诊断的生物标志物以及发现治疗酒精依赖的新药物将非常有帮助。申请人提出了一项基于人群的研究来测试基因与疾病之间的关联，一项基因组控制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），一项表型控制研究来测试表型特异性任何预期的关联，以及用于测试关联的人群特异性的人口控制研究。最后，提出一项基于家庭的研究来证实基于人群的研究结果。这些基因内的 240 个标记将在总共 2664 名受试者中进行基因分型（初步研究中已研究了 27 个标记，其中许多标记与酒精依赖呈正相关）。总之，本研究将鉴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，并为新药提供潜在靶点。