Genome-wide studies of linkage disequilibrium have revealed that most of the human genome is covered by blocks of varying length within which marker to marker linkage disequilibrium is very high. Each haplotype block is separated by recombination sites. There are usually only 3-6 haplotypes with greater than 5% frequency within each block. 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, and one admixed population, 900 African Americans, for several candidate genes for alcoholism and anxiety, including the chromosome 4 cluster of GABAA receptor genes that are predominantly expressed in the brain reward circuitry. Haplotype-based analyses revealed that in Caucasian and Plains Indian men 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 both populations (men and women) we found GABRG1 haplotype linkage to alcoholism. Moreover, long-distance ancestral haplotypes spanning GABRG1 and GABRA2 were associated with alcoholism; this association was determined by GABRG1 (Enoch et al, in press). The African Americans had two unique GABRA2 haplotypes, one conferred resilience to addiction and the other predicted heroin addiction (Enoch et al, submitted). ? ? We have previously shown that the functional COMT Val158Met polymorphism is associated with trait anxiety in women (Enoch et al, 2003). We have recently shown that individuals with anxiety disorders comorbid with alcoholism and/or depression have the greatest proportion of COMT Met158 and BDNF Met66 alleles compared with individuals with pure anxiety, alcoholism, major depression or no diagnosis (Enoch et al, 2008). Furthemore, in Plains Indians, the COMT Met158 allele is associated with better long-term memory, working memory and attention (Enoch et al, in press).? ? Other SNP and haplotype analyses are being undertaken in other alcoholism/anxiety candidate genes. For example, preliminary work shows an association between a functional HTR3B SNP and alcoholism in African American men.
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