Controls for Association Studies of Alcoholism

酗酒关联研究的控制

• 批准号: 7881139
• 负责人: Kenneth K. KIDD
• 金额: $ 9.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881139
• 关键词: Affect; Africa; Alcohol consumption; Alcohol dehydrogenase; Alcoholism; Alcohols; Alleles; Amerindian; Asians; Beds; China; Chinese People; Chromosomes; Collaborations; Complex; Data; Data Analyses; Databases; Development; Disease; Enzymes; Ethanol Metabolism; European; Family; Far East; Frequencies; Gene Cluster; Gene Conversion; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; German population; Gorilla gorilla; Grant; Haplotypes; High Prevalence; Human; Human Genetics; India; Individual; Linkage Disequilibrium; MHC Class I Genes; Macaca mulatta; Methods; Morbidity - disease rate; Mutation; National Institute on Alcohol Abuse and Alcoholism; Native Americans; Nucleic Acid Regulatory Sequences; Pan Genus; Papio; Patients; Pattern; Pongidae; Pongo pygmaeus; Population; Population Genetics; Population Study; Predisposition; Primates; Public Health; Recording of previous events; Relative (related person); Research; Research Personnel; Risk; Role; Sampling; Site; Surveys; Test Result; Testing; Variant; Work; base; genetic variant; problem drinker; protective effect

DESCRIPTION (provided by applicant): Alcoholism is a significant public health problem because of its prevalence and the high morbidity to patients and high impact on their relatives. The alcohol dehydrogenase (ADH) cluster of genes and the aldehydedehydrogenase 2 locus. (ALDH2) are known to affect alcohol metabolism and the genetic susceptibility to alcoholism in some populations, primarily populations of East Asian ancestry. Our new haplotype analyses of the ADH gene cluster show significant linkage disequilibrium and attribute the effect on alcoholism in the Chinese sample analyzed to only one haplotype. Recent work by others similarly finds a single relevant haplotype at the ALDH2 locus. Other data suggest that alleles not yet identified at these loci may be relevant to alcoholism and/or alcohol metabolism in Asian and other populations. Considered with the realization of the complexity of global human genetic diversity (developed in part from previous work on this grant), these data support undertaking a comprehensive global survey of genetic variation at the ADH gene cluster and at the ALDH2 locus. Therefore we propose to extend the study of the haplotypes across these entire regions, by identifying polymorphisms encompassing the entire region with each gene covered at molecularly short distances and type the most informative markers on at least 38 in-lab population samples representing all major parts of the world. A combination of known and new makers encompassing ALDH2 will similarly be studied. Collaborators in China, India, and Africa will continue to help develop better coverage of populations in their regions for ADH and ALDH2 haplotypes. Studies of other higher primates (chimpanzees, gorillas, orangutans) to determine the direction of mutation for each human polymorphism will illuminate the evolutionary origins of the existing variation. We will continue to collaborate with other researchers to examine these haplotypes in three different sets of individuals with alcoholism, one Chinese, one German, and one Australian (Northern European ancestry) and communicate our polymorphism and haplotype data to collaborators working on the COGA and NIAAA linkage studies of alcoholism. Thus, this complex and multifaceted project will provide the necessary population genetic basis for further studies of the ADH and ALDH2 loci as related to alcoholism and will undertake different applications to alcoholism and alcohol metabolism using haplotype approaches. Indications of the importance to alcoholism of different genetic variants and of which haplotypes may harbor cryptic but functionally relevant variation will result from these studies.

描述（由申请人提供）： 酒精中毒是一个重大的公共卫生问题，因为它的流行和对患者的高发病率高以及对其亲戚的高影响。基因的酒精脱氢酶（ADH）簇和醛氢化氢酶2基因座。 （ALDH2）已知会影响某些人群中的酒精代谢和对酒精中毒的遗传敏感性，主要是东亚血统的人群。我们对ADH基因群集的新单倍型分析表明，在分析的中国样本中，对酒精中毒的影响显着不平衡，只有一种单倍型。其他人最近的工作类似地发现了ALDH2基因座的单一相关单倍型。其他数据表明，在这些基因座尚未确定的等位基因可能与亚洲和其他人群中的酒精中毒和/或酒精代谢有关。考虑到实现全球人类遗传多样性的复杂性（部分是根据先前在这笔赠款上的工作开发的），这些数据支持对ADH基因群和ALDH2基因座进行了全面的全球遗传变异调查。因此，我们建议通过鉴定包含整个区域的多态性，以分子短距离覆盖的每个基因，并键入至少38个表现的最有用的标志物，从而扩展整个区域的单倍型的研究，并键入最有用的标记。 世界所有主要地区。同样会研究已知和新的制造商的结合。中国，印度和非洲的合作者将继续帮助在其ADH和ALDH2单倍型地区更好地覆盖其地区。对其他高级灵长类动物（黑猩猩，大猩猩，猩猩）确定每个人类多态性突变方向的研究将阐明现有变异的进化起源。我们将继续与其他研究人员合作，以三种不同的酒精中毒，一组中国人，一个德国和一个澳大利亚人（北欧血统）来检查这些单型，并将我们的多态性和单倍型数据传达给在COGA和NIAAA链接研究的合作者。因此，这个复杂而多方面的项目将为与酒精中毒有关的ADH和ALDH2基因座的进一步研究提供必要的人口遗传基础，并将使用单倍型方法对酒精中毒和酒精代谢进行不同的应用。这些研究的迹象表明，单倍型可能具有神秘但功能相关的变异的重要性。

项目成果

DRD2 haplotypes containing the TaqI A1 allele: implications for alcoholism research.

• DOI: 10.1111/j.1530-0277.1996.tb01674.x
• 发表时间: 1996-06
• 期刊: Alcoholism, clinical and experimental research
• 作者: Kenneth K. Kidd;A. Pakstis;C. Castiglione;J. Kidd;W. Speed;David Goldman;W. Knowler;R. Lu;Batsheva Bonne-Tamir

Homozygosity by descent for a rare mutation in the myophosphorylase gene is associated with variable phenotypes in a Druze family with McArdle disease.

肌磷酸化酶基因中罕见突变的血统纯合性与患有麦卡德尔病的德鲁兹家族的可变表型相关。

• DOI: 10.1136/jmg.34.5.391
• 发表时间: 1997
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Iyengar,S;Kalinsky,H;Weiss,S;Korostishevsky,M;Sadeh,M;Zhao,Y;Kidd,KK;Bonne-Tamir,B
• 通讯作者: Bonne-Tamir,B

Distribution and frequency of a polymorphic Alu insertion at the plasminogen activator locus in humans.

人类纤溶酶原激活物基因座多态性 Alu 插入的分布和频率。

• DOI: 10.1007/bf02346186
• 发表时间: 1996
• 期刊: Human genetics
• 影响因子: 5.3
• 作者: Tishkoff,SA;Ruano,G;Kidd,JR;Kidd,KK
• 通讯作者: Kidd,KK

Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms.

分析跨物种聚合酶链反应产物以推断人类多态性的祖先状态。

• DOI: 10.3109/10425179809034076
• 发表时间: 1998
• 期刊: DNA sequence : the journal of DNA sequencing and mapping
• 作者: Iyengar,S;Seaman,M;Deinard,AS;Rosenbaum,HC;Sirugo,G;Castiglione,CM;Kidd,JR;Kidd,KK
• 通讯作者: Kidd,KK

Evolution of a D2 dopamine receptor intron within the great apes and humans.

类人猿和人类 D2 多巴胺受体内含子的进化。

• DOI: 10.3109/10425179809034074
• 发表时间: 1998
• 期刊: DNA sequence : the journal of DNA sequencing and mapping
• 作者: Deinard,AS;Kidd,KK
• 通讯作者: Kidd,KK