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.
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