DRD2 HAPLOTYPES CONTAINING THE TAQI A1 ALLELE - IMPLICATIONS FOR ALCOHOLISM RESEARCH

In recent years, a possible role of the dopamine D-2 receptor (DRD2) l ocus in the etiology of alcoholism has been the focus of considerable attention. The literature now contains a mix of association studies wi th positive and negative conclusions. Various methodological flaws und ermine the claims in many of the studies that conclude a positive asso ciation exists between alcoholism and the DRD2A1 allele at the Taql ' 'A'' site. Although the studies with negative findings have more often come from studies using better analytic methodology, satisfactory res olution of whether or not genetic variation at the DRD2 locus plays so me role in the etiology of alcoholism is unlikely to come from additio nal studies of the kind conducted thus far; an approach enlightened by a more thorough understanding of the population genetics of DRD2 and the phylogenetic origins of the DRD2 alleles is one alternative. If ge netic variation at the DRD2 locus affects susceptibility to alcoholism , then such variation has a mutational and evolutionary history that c an be traced with the aid of the various genetic polymorphisms that ha ve been identified at the DRD2 locus. In this study, a third Taql rest riction fragment-length polymorphism at DRD2, the Taql ''D'' site, has been converted to polymerase chain reaction-based typing and its freq uencies determined in 22 populations from around the world. Haplotypes defined by the polymorphisms at the Taql ''B'' and ''A'' sites, and t he short tandem repeat polymorphism in intron 2 have been constructed and the diversity of haplotypes containing the DRD2A1 allele examined for all 22 populations. The ancestral origins of the three Taql polym orphisms have also been determined by sequencing the homologous region s in other higher primates. Because A1-containing haplotypes in popula tions of European, Middle Eastern, and African origin show considerabl e diversity within and among populations, properly designed associatio n studies in populations descended from those areas of the world need to use haplotypes, not a singleallelic system, and need to use appropr iate methods to compensate for the near impossibility of genetically m atching unrelated control samples.