Haplotype and Single-locus Analyses for Alcoholism and A

最近，连锁不平衡的全基因组研究已经揭示，大多数人类基因组被不同长度的区块覆盖，其中标记与标记连锁不平衡非常高，并且其中仅观察到少数常见的单倍型（通常，具有大于5%频率的3 - 5个单倍型），其被重组位点分开。这些单倍型反映了从一个单一的，古老的祖先染色体的后裔。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获了这些区域内遗传变异的大部分信息，并且可以仅使用少量的SNP（通常为3至8个）来鉴定单倍型。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地区的每一个变异。 我们对两个种族不同的人群分离株进行了基因分型，大约500名芬兰高加索人和400名平原美洲印第安人，用于酒精中毒和焦虑的几个候选基因。这些包括染色体4簇GABAA受体基因和神经肽甘丙肽加上3个甘丙肽受体基因，这些基因与严重应激反应有关。基于单倍型的分析显示，在来自这两个群体的男性中，GABRA 2单倍型与酒精中毒之间存在关联，该关联由伤害回避（HA）介导，HA是焦虑的维度测量（以诺等人，2006）。此外，在两个人群（男性和女性）中，我们发现GABRB 1和GABRG 1的单倍型与酒精中毒有关。此外，与GABRB 1和GABRG 1相关的酒精中毒风险是相加的。在两个群体中，甘丙肽单倍型与酒精中毒相关，其也可能由焦虑介导（Belfer等人，2006）甘丙肽在GALR3而不是其他两种受体上的作用似乎是与酒精中毒相关的关键（Belfer等人，出版中）。 我们先前已经证明功能性COMT Val 158 Met多态性与女性焦虑相关（以诺等人，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，Met 158 "焦虑"等位基因可以防止酗酒，在女性中，它也可以防止吸烟（以诺等人，2006）。其他酒精中毒/焦虑症候选基因的单核苷酸多态性和单倍型分析正在进行中。

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.