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

我们正在寻找基因位点， 酗酒倾向和相关行为， 利用500多个基因进行遗传连锁和图谱分析， 高度多态性DNA标记位点。这些位点跨越了 非性染色体平均间隔小于10 厘摩到目前为止，我们已经完成了超过260，000个轨迹 打字，主要是美国印第安人和芬兰人。我们有 进行了一次全常染色体基因组扫描， 美国西南部印第安部落的酒精依赖 517个常染色体微卫星位点的基因型与临床 对152名属于扩大的 家系，形成172个同胞对。有证据表明 出现了两个基因组区域的连锁;两个区域都含有 神经遗传学候选基因最好的证据是 D11 S1984位于染色体11 p上，靠近DRD 4 多巴胺受体基因D4 S3242打开时观察到良好证据 染色体4p，靠近β 1 GABA受体基因。 在芬兰语中， 我们已经完成了超过70%的全基因组搜索， 连锁和候选基因，并测试与 Y染色体上的DNA标记。我们的基因扫描 揭示了三个染色体区域， 导致酒精依赖的脆弱性，一个在染色体上 3，另一个在染色体5上，最后一个在染色体11上。的 在这些区域中的每一个中的联系的证据由LOD支持 (log比值比（odds ratio）超过3.0。这是公认的卢比孔河 用于连锁分析的统计显著性。另外我们有 证明了Y染色体DNA标记 酒精依赖和反社会人格障碍我们发现 酒精中毒与3组Y- 这些染色体因其突变历史而密切相关。 对于具有神经生物学功能的候选基因，我们发现 有证据表明反社会者与 酒精中毒型人格障碍与染色体 6 5-羟色胺受体基因HTR 1B。我们还发现了 ASPD与酒精中毒之间的联系和关联 紧密连锁的标记位点D 6S 286的多态性。

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 260,000 locus typings, primarily on American Indians and Finns. We have performed a whole autosomal genome scan for genetic linkage to alcohol dependence in the Southwestern American Indian tribe. Genotypes at 517 autosomal microsatellite loci and clinical evaluations were available for 152 subjects belonging to extended pedigrees and forming 172 sib-pairs. Highly suggestive evidence for linkage emerged for two genomic regions; both regions harbor neurogenetic candidate genes. The best evidence is seen with D11S1984 on chromosome 11p, in close proximity to the DRD4 dopamine receptor gene. Good evidence is seen with D4S3242 on chromosome 4p, nearby the beta1 GABA receptor gene. In Finns, we have completed over 70% of a full genome search, tested for linkage 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. The evidence for linkage in each of these regions is supported by a LOD (log odds ratio) of over 3.0. This is the generally accepted rubicon for statistical significance in linkage analysis. 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. For the candidate genes with neurobiological function, we find evidence for genetic linkage and association between antisocial personality disorder (ASPD) 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.