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.
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