Linkage disequilibrium at the ADH2 and ADH3 loci and risk of alcoholism

Two of the three class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode known functional variants that act on alcohol with different efficie ncies. Variants at both these genes have been implicated in alcoholism in s ome populations because allele frequencies differ between alcoholics and co ntrols. Specifically, controls have higher frequencies of the variants with higher V-max (ADH2*2 and ADH3*1). In samples both of alcoholics and of con trols from three Taiwanese populations (Chinese, Ami, and Atayal) we found significant pairwise disequilibrium for all comparisons of the two function al polymorphisms and a third, presumably neutral, intronic polymorphism in ADH2. The class I ADH genes all lie within 80 kb on chromosome 4; thus, var iants are not inherited independently, and haplotypes must be analyzed when evaluating the risk of alcoholism. In the Taiwanese Chinese we found that, only among those chromosomes containing the ADH3*1 variant (high V-max), t he proportions of chromosomes with ADH2*1 (low V-max) and those with ADH2*2 (high V-max) are significantly different between alcoholics and controls ( p < 10(-5)) The proportions of chromosomes with ADH3*1 and those with ADH3* 2 are not significantly different between alcoholics and controls, on a con stant ADH2 background (with ADH2*1, P = .83; with ADH2*2, P = .53). Thus, t he observed differences in the frequency of the functional polymorphism at ADH3, between alcoholics and controls, can be accounted for by the disequil ibrium with ADH2 in this population.