DRD2 DOPAMINE RECEPTOR GENOTYPE, LINKAGE DISEQUILIBRIUM, AND ALCOHOLISM IN AMERICAN-INDIANS AND OTHER POPULATIONS

We defined interpopulation differences in the frequency of the dopamin e D2 receptor DRD2/Taq1 A1 allele, which has previously been associate d with alcoholism. Frequencies of the Al 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), 0.6 3 (+/- 0.07) in Jemez Pueblo Indians (n = 23), and 0.80 (+/- 0.04) in Cheyenne Indians (n = 52). The existence of large interpopulation diff erences in the frequency of the Taq1 alleles suggests that association s to disease status could readily be generated or masked if disease an d control groups were uneven in ethnic composition. To address the pos sibility that the 4-fold higher frequency of the Al allele in Cheyenne Indians was related to an increased vulnerability to alcoholism in th at population, 47 Cheyenne Indians were psychiatrically interviewed an d blind-rated. However, there was no significant difference between in terviewed controls (0.73 +/- 0.06, n = 24), subjects with alcoholism a nd/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 popu lations and could place an upper bound on the strength of an associati on. 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' regi on of the gene, was determined in three populations. The normalized di sequilibrium values were 0.36 in U.S. Caucasians (n = 48), 0.34 in Fin ns (n = 86), and 0.78 in Cheyenne Indians (n = 34).