DRD2 Dopamine Receptor Genotype, Linkage Disequilibrium, and Alcoholism in American Indians and Other Populations

We defined interpopulation differences in the frequency of the dopamine D2 receptor DRD2/Taq1 A1 allele, which has previously been associated with alcoholism. Frequencies of the A1 allele in unrelated subjects were 0.18 to 0.20 (se = 0.02 to 0.03) in several Caucasian populations previously assessed, 0.38 (±0.05) in American Blacks (n= 44), 0.63 (±0.07) in Jemez Pueblo Indians (n= 23), and 0.80 (± 0.04) in Cheyenne Indians (n= 52). The existence of large interpopulation differences in the frequency of the Taq1 alleles suggests that associations to disease status could readily be generated or masked if disease and control groups were uneven in ethnic composition. To address the possibility that the 4‐fold higher frequency of the A1 allele in Cheyenne Indians was related to an increased vulnerability to alcoholism in that population, 47 Cheyenne Indians were psychiatrically interviewed and blind‐rated. However, there was no significant difference between interviewed controls (0.73 ± 0.06, n= 24), subjects with alcoholism and/or drug abuse (0.74 ± 0.06, n= 23) and noninterviewed population controls (0.87 ± 0.05, n= 20). Legitimate association of the DRD2/Taq1 allele to alcoholism would presumably require it to be in linkage disequilibrium (nonrandom association) with a functional mutation at DRD2 or elsewhere. The level of disequilibrium would vary between populations and could place an upper bound on the strength of an association. To provide a model for the extent and variation of disequilibrium at DRD2, the level of linkage disequilibrium between the Taq1 RFLP and a second DRD2 polymorphism, the SSCP variant in the immediate 3’region of the gene, was determined in three populations. The normalized disequilibrium values were 0.36 In U.S. Caucasians (n= 48), 0.34 in Finns (n= 86), and 0.78 in Cheyenne Indians (n= 34).