Genetic variation and linkage disequilibrium in the human alcohol dehydrogenase genes: Implications of the evolutionary history of a gene family in humans

The nature of genetic variation and the nature and extent of linkage disequilibrium in the alcohol dehydrogenase (ADH) genes in >30 populations from around the world was studied. These analyses were undertaken to determine the implications of the population genetics of the ADH genes in studies of human evolution and the epidemiology of alcoholism.; We found that genetic variation in the ADH genes is generally similar within large geographic regions with a few exceptions such as in populations that have undergone strong founder effects. Between geographic regions, there are differences in the nature of variation, especially between the east Asian samples we studied and all other geographic regions. In contrast to the nature of variation, linkage disequilibrium is strong in all populations across the Class I ADH genes. While there is no clear overall pattern, pairwise linkage disequilibrium between some Class I ADH SNPs and the ADH4 and ADH7 SNPs is weak but significant in some populations. Tests for evidence of linkage disequilibrium across the segments between the Class I ADH SNPs taken as a whole and the ADH4 and ADH7 SNPs are insignificant except for a few populations.; Using a haplotype-based method of testing for independent functional effects of polymorphic sites under conditions of linkage disequilibrium for a subset of the SNPs, we found that previous interpretations of association studies claiming that the ADH1B Arg47His and ADH1C Ile349Val polymorphisms have an independent effect need to be re-examined. Based on the impact of linkage disequilibrium on the interpretation of association studies and the extent of linkage disequilibrium in some populations, it seems prudent for future studies of the role of the ADHs in the protection against alcoholism to test and account for linkage disequilibrium within the ADH gene family as a whole on a sample-by-sample and site-by-site basis. Indeed, we have found a new SNP 6bp downstream from the frequently studied ADH1C Ile349Val site in ADH1C which results in a Pro-Thr amino acid substitution and is almost exclusive to Amerindians. This site may be relevant to protection against alcoholism in Amerindian populations but has been previously unexamined.