Haplotype-Based Analyses for Alcoholism and Anxiety

最近，对基因组相邻区域中高密度单核苷酸多态性（SNP）之间的连锁不平衡（等位基因关联）的研究揭示了一种简单的长度不同的区块模式，在该模式上仅观察到几种常见的单倍型（通常，3-5种频率大于或等于5%的单倍型），它们被重组位点分开。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。单倍型方法的主要优点是，常见的单倍型捕获了大区域内的大部分遗传变异，并且可以仅通过少量的SNP（通常为3至8个）进行鉴定。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4号染色体上的GABAA受体基因簇和神经肽甘丙肽，甘丙肽与严重的应激反应有关。基于单倍型的分析显示，至少在来自这两个群体的男性中，GABRA 2单倍型和酗酒之间的关联是由伤害回避（HA）介导的，伤害回避是焦虑的维度测量（以诺等人，提交）。在这两个群体中，我们还发现单倍型连锁酗酒的近端部分GABRB 1，包括调控区。在这两个人群中，甘丙肽单倍型与酒精中毒相关，这也可能是由焦虑介导的（Belfer等人，出版中）。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, studies of linkage disequilibrium (allelic association) between high densities of single nucleotide polymorphisms (SNPs) across contiguous regions of the genome have revealed a simple pattern of blocks of varying length over which only a few common haplotypes (in general, 3-5 haplotypes with greater than, or equal to, 5% frequency) are observed, separated by recombination sites. These haplotypes reflect descent from a single, ancient ancestral chromosome. The main advantage of haplotype methods is that common haplotypes capture most of the genetic variation across large regions and can be identified by 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 that has been implicated in response to severe stress. Haplotype-based analyses revealed that, at least in men from these two populations, an association between GABRA2 haplotypes and alcoholism is mediated by harm avoidance (HA), a dimensional measure of anxiety (Enoch et al, submitted). In both populations we also found haplotype linkage to alcoholism in the proximal part of GABRB1 that includes the regulatory region. There was a galanin haplotpye association with alcoholism in both populations that may also be mediated by anxiety (Belfer et al, in press). Genotyping of SNPs and haplotype analyses in other alcoholism/anxiety candidate genes is being undertaken.