GENE MAPPING AND LINKAGE STUDIES WITH SHORT TANDEM REPEAT (STR) MARKERS

短串联重复 (STR) 标记的基因作图和连锁研究

• 批准号: 6288628
• 负责人: Jeffrey C. LONG
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6288628
• 关键词: Native Americans; Scandinavian; alcohol dehydrogenase; alcoholism /alcohol abuse; antisocial personality; behavioral /social science research tag; behavioral genetics; clinical research; disease /disorder proneness /risk; enzyme activity; genetic markers; genetic polymorphism; genotype; human genetic material tag; human subject; linkage mapping; nucleic acid repetitive sequence; sex chromosomes

We are searching for genetic loci that contribute to the predisposition to alcoholism and related behaviors by conducting genetic linkage and mapping analysis using over 500 highly polymorphic DNA marker loci. These loci span all of the non-sex chromosomes at an average interval less than 10 centimorgans. To date, we have completed over 300,000 locus typings, primarily on American Indians and Finns. We have performed a whole autosomal genome scan for genetic linkage to alcohol dependence in a Southwestern American Indian tribe. The best evidence for linkage is seen with D11S1984 on chromosome 11p, in close proximity to several candidate genes with neurobiological functions. These candidate genes include the DRD4 dopamine receptor gene, the tyrosine hydroxylase gene, and the tryptophan hydroxylase gene. Good evidence for linkage is also seen with D4S3242 on chromosome 4p, nearby the beta1 GABA receptor gene. The chromosome 11 findings were followed up in the past year by genotyping a high resolution map on an expanded sample of subjects from the same Southwestern Indian population. The high resolution genetic map includes polymorphisms within the DRD4 and tyrosine hydroxylase genes as well as STR markers closely linked to these candidate genes. We are also developing statistical approaches and software for identifying which specific polymorphisms from a set of closely linked loci are responsible for altering an individuals vulnerability to disease. So far, we have succeeded in identifying polymorphisms associated with disease status, but we have not identified specific variants altering vulnerability. In Finns, we have completed much of a full genome search, tested for linkage to marker loci and to candidate genes, and tested for association with DNA markers on the Y chromosome. Our genome scan has revealed three chromosomal regions that are likely to harbor genes rendering vulnerability to alcohol dependence, one on chromosome 3, another on chromosome 5, and the last on chromosome 11. In addition, we have demonstrated association between Y chromosome DNA markers and alcohol dependence and antisocial personality disorder. We find a significant association between alcoholism and 3 groups of Y- chromosomes that are closely related by their mutational histories. Interestingly, there is no association between Y chromosomes and antisocial personality disorder after the comorbid effects of alcohol dependence have been removed. However, we find evidence for genetic linkage and association between antisocial personality disorder (ASPD) comorbid with alcoholism and the chromosome 6 serotonin receptor gene HTR1B. We also find evidence for linkage and association between ASPD with alcoholism and a polymorphism in the closely linked marker locus D6S286. These findings are confirmed by multipoint linkage analyses and by independent observation in the Southwestern Indian sample. - gene mapping (human), neurosciences, drinking patterns/causes, molecular genetics - Human Subjects: Interview, Questionaires, or Surveys Only

我们正在寻找通过使用500多个高度多态性DNA标记基因座进行遗传连锁和映射分析，从而有助于酒精中毒和相关行为的遗传基因座。这些基因座的平均间隔小于10厘米。迄今为止，我们已经完成了300,000多个基因座键入，主要是在美洲印第安人和芬兰人上。我们已经进行了整个常染色体基因组扫描，以与西南美洲印第安人部落的遗传联系与酒精依赖性。与D11S1984在11p染色体上可以看到连锁的最佳证据，与具有神经生物学功能的几个候选基因非常接近。这些候选基因包括DRD4多巴胺受体基因，酪氨酸羟化酶基因和色氨酸羟化酶基因。在4p染色体上，D4S3242在Beta1 GABA受体基因附近还可以看到D4S3242的良好证据。在过去的一年中，通过在同一西南部印度人口的扩展样本中绘制了高分辨率图，在过去一年中进行了11个染色体发现。高分辨率遗传图包括DRD4和酪氨酸羟化酶基因内的多态性以及与这些候选基因紧密相关的STR标记。我们还正在开发统计方法和软件，以识别一组紧密联系的基因座的哪些特定多态性负责改变个人易受疾病的脆弱性。到目前为止，我们已经成功地识别了与疾病状况相关的多态性，但是我们尚未确定改变脆弱性的特定变体。在Finns中，我们已经完成了许多完整的基因组搜索，并测试了与标记基因座和候选基因的联系，并测试了与Y染色体上的DNA标记相关的。我们的基因组扫描揭示了三个染色体区域，这些区域可能具有使依赖酒精依赖性的脆弱性的基因，一种是染色体，另一个是在5号染色体上，最后一个在11号染色体上。此外，我们还证明了Y染色体DNA标记和酒精依赖性和抗性性人性疾病之间的y染色体染色体之间的关联。我们发现酒精中毒与3组Y-染色体之间存在显着关联，这些染色体与它们的突变历史密切相关。有趣的是，Y染色体和反社会人格障碍之间的依赖性依赖性疾病的染色体和反社会人格障碍之间没有关联。但是，我们发现反社会人格障碍（ASPD）与酒精中毒与6-羟色胺受体基因HTR1B的遗传联系和关联的证据。我们还发现了在紧密联系的标记基因座D6S286中，ASPD与酒精中毒与多态性之间的联系和关联的证据。这些发现通过多点连接分析和西南印度样本中的独立观察证实。 - 基因映射（人），神经科学，饮酒模式/原因，分子遗传学 - 人类受试者：访谈，问题或调查