Haplotype-Based Analyses for Alcoholism and Anxie

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。 我们已经使用基于单倍型的分析，以检测与酒精中毒和焦虑，主要是在4号染色体簇的GABAA受体基因。我们发现，在两个不同种族的人群，芬兰高加索人和平原美洲印第安人，酗酒者与高维焦虑（伤害回避（HA））有最丰富的GABAAa 2单倍型的频率最高，非酗酒者的中间，低HA酗酒者有最低的频率，这种单倍型。在一个相反的关系，低HA酗酒者有较高的频率较低的丰富的单倍型，非酗酒者的中间和高HA酗酒者有较低的频率。按性别进行的分析表明，这一发现仅限于男子。与此相反，单倍型频率在非酗酒者与高和低HA没有差异，在任何一个样本。已完成4号染色体复合体中GABAAa 4和GABAAb 1以及5号染色体复合体中GABAAa 6中SNP的基因分型，已鉴定单倍型块，并正在进行基于单倍型的关联分析。其他酒精中毒/焦虑症候选基因，特别是甘丙肽和痛敏肽的SNP基因分型正在进行中。

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 used haplotype-based analyses in order to detect associations with alcoholism and anxiety, primarily in the chromosome 4 cluster of GABAA receptor genes. We have found that in two ethnically diverse populations, Finnish Caucasians and Plains American Indians, alcoholics with high dimensional anxiety (harm avoidance (HA)) had the highest frequency of the most abundant GABAAa2 haplotype, non-alcoholics were intermediate, and low HA alcoholics had the lowest frequency of this haplotype. In an inverse relationship, low HA alcoholics had higher frequencies of the less abundant haplotypes, non-alcoholics were intermediate and high HA alcoholics had lower frequencies. Analysis by sex showed that this finding was confined to men. In contrast, haplotype frequencies in non-alcoholics with high and low HA did not differ in either sample. Genotyping of SNPs in GABAAa4 and GABAAb1 in the chromosome 4 complex, and GABAAa6 in the chromosome 5 complex has been completed, haplotype blocks have been identified and haplotype-based association analyses are underway. Genotyping of SNPs in other alcoholism/anxiety candidate genes, in particular galanin and nociceptin, is being undertaken.