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

我们正在通过使用超过500个高度多态性的DNA标记位点进行遗传连锁和作图分析，寻找导致酗酒易感性和相关行为的遗传位点。这些位点以小于10厘米的平均间隔分布在所有的非性染色体上。到目前为止，我们已经完成了超过30万个基因座类型，主要是在美洲印第安人和芬兰人身上。我们对美国西南部印第安部落的酒精依赖基因进行了全常染色体基因组扫描。这种联系的最佳证据是11p染色体上的D11S1984，它与几个具有神经生物学功能的候选基因非常接近。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。在染色体4p上的D4S3242上也发现了良好的连锁证据，该位点位于beta1 GABA受体基因附近。对11号染色体的发现，在过去的一年里，对来自印度西南部同一人群的扩大样本进行了高分辨率的基因分型。高分辨率遗传图谱包括DRD4和酪氨酸羟化酶基因内的多态性，以及与这些候选基因密切相关的STR标记。我们还在开发统计方法和软件，以确定来自一组紧密相连的基因座的哪些特定多态性负责改变个体对疾病的易感性。到目前为止，我们已经成功地确定了与疾病状态相关的多态性，但我们还没有确定改变易感性的特定变异。在芬兰人中，我们已经完成了大部分全基因组搜索，测试了与标记位点和候选基因的联系，并测试了与Y染色体上DNA标记的关联。我们的基因组扫描显示，有三个染色体区域可能含有导致酒精依赖的基因，一个在3号染色体上，一个在5号染色体上，最后一个在11号染色体上。此外，我们已经证明了Y染色体DNA标记与酒精依赖和反社会人格障碍之间的关联。我们发现酒精中毒和3组Y染色体之间有显著的关联，它们的突变史密切相关。有趣的是，在酒精依赖的共病效应被消除后，Y染色体和反社会人格障碍之间没有关联。然而，我们发现反社会人格障碍（ASPD）与酒精中毒共病与6号染色体5 -羟色胺受体基因HTR1B之间存在遗传联系和关联的证据。我们还发现了反社会人格障碍与酒精中毒之间的联系和关联，以及密切相关的标记位点D6S286的多态性。这些发现被多点联系分析和独立观察在西南印度样本证实。-基因定位（人类），神经科学，饮酒模式/原因，分子遗传学-人类受试者：访谈，问卷调查或仅限调查

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