Haplotype and Single-locus Analyses for Alcoholism and A

最近，对连锁不平衡的全基因组研究表明，大部分人类基因组被不同长度的块覆盖，其中标记与标记之间的连锁不平衡非常高，并且在其中仅观察到少数常见的单倍型（通常为3-5个单倍型，频率大于5%），由重组位点分开。这些单倍型反映了一个单一的，古老的祖先染色体的血统。单倍型方法用于连锁和关联研究的主要优点是，这些共同的单倍型捕获了这些区域内遗传变异的大部分信息，并且单倍型可以仅使用少量的SNPs（通常为3到8个）来识别。因此，基于单倍型的病例对照研究可以发现与疾病或行为的关联，而不必在该地区发现和测试每一个变异。

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.