Haplotype and Single-locus Analyses for Alcoholism and A

酗酒和 A 的单倍型和单基因座分析

• 批准号: 7317723
• 负责人: mary anne enoch
• 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/7317723
• 关键词: Haplotype; Single; locus; Analyses; Alcoholism

Recently, genome-wide studies of linkage disequilibrium have revealed that most of the human genome is covered by blocks of varying length in within which marker to marker linkage disequilibrium is very high and within which only a few common haplotypes (in general, 3-5 haplotypes with greater than 5% frequency) are observed, separated by recombination sites. These haplotypes reflect descent from a single, ancient ancestral chromosome. The main advantage of haplotype methods for linkage and association studies is that these common haplotypes capture most of the information on genetic variation within these regions and the haplotypes can be identified using only a small number of SNPs, usually 3 to 8. Thus haplotype-based case-control studies can detect associations with disease or behavior without having to find and test every single variant in the region. We have genotyped two ethnically diverse population isolates, approximately 500 Finnish Caucasians and 400 Plains American Indians, for several candidate genes for alcoholism and anxiety. These include the chromosome 4 cluster of GABAA receptor genes and the neuropeptide galanin plus the 3 galanin receptor genes that have been implicated in response to severe stress. Haplotype-based analyses revealed that in men from these two populations there was an association between GABRA2 haplotypes and alcoholism that is mediated by harm avoidance (HA), a dimensional measure of anxiety (Enoch et al, 2006). In addition, in both populations (men and women) we found haplotype linkage to alcoholism in both GABRB1 and GABRG1. Moreover, alcoholism risks associated with GABRB1 and GABRG1 were additive. There was a galanin haplotype association with alcoholism in both populations that may also be mediated by anxiety (Belfer et al, 2006).The effects of galanin at GALR3 and not the other two receptors appear to be key for the association with alcoholism (Belfer et al, in press). We have previously shown that the functional COMT Val158Met polymorphism is associated with anxiety in women (Enoch et al, 2003). We have now shown that within the Plains Indians (who have a binge pattern of drinking) the Met158 'anxiety' allele is protective against alcoholism and in women it also protects against smoking (Enoch et al, 2006). Genotyping of SNPs and haplotype analyses in other alcoholism/anxiety candidate genes is being undertaken.

最近，全基因组的连锁不平衡研究表明，人类基因组的大部分被不同长度的区块覆盖，其中标记与标记的连锁不平衡非常高，其中只观察到少数常见的单倍型(一般有3-5种单倍型，频率大于5%)，由重组位点分隔。这些单倍型反映了单个古老祖先染色体的后代。用于连锁和关联研究的单倍型方法的主要优点是，这些常见的单倍型捕捉了这些区域内遗传变异的大部分信息，并且只需使用少量的SNP(通常为3到8个)就可以识别单倍型。因此，基于单倍型的病例对照研究可以检测与疾病或行为的关联，而不必发现和测试该区域的每一个变异。 我们已经对两个不同种族的人群分离株，大约500名芬兰高加索人和400名美洲平原印第安人，进行了几个酗酒和焦虑的候选基因的基因分型。这些基因包括GABAA受体基因的第4染色体簇和神经肽Galanin加上与严重应激反应有关的3个Galanin受体基因。基于单倍型的分析显示，在这两个群体的男性中，GABRA2单倍型与酒精中毒之间存在关联，这是通过伤害避免(HA)介导的，HA是焦虑的一种维度测量(Enoch等人，2006年)。此外，在这两个群体(男性和女性)中，我们都在Gabrb1和GABRG1中发现了单倍型与酒精中毒的联系。此外，与Gabrb1和GABRG1相关的酒精中毒风险是相加的。在两个人群中都存在甘丙素单倍型与酒精中毒的关联，这也可能是由焦虑所介导的(Belfer等人，2006)。甘丙肽在GALR3而不是其他两个受体上的作用似乎是与酒精中毒关联的关键(Belfer等人，在出版社中)。 我们先前已经证明功能性COMT Val158Met多态与女性焦虑相关(Enoch等人，2003)。我们现在已经证明，在平原印第安人(他们有酗酒的模式)中，Met158‘焦虑’等位基因对酒精中毒有保护作用，在女性中也能防止吸烟(Enoch等人，2006年)。其他酗酒/焦虑候选基因的SNPs基因分型和单倍型分析正在进行中。