LINKAGE DISEQUILIBRIA AT THE D-2 DOPAMINE-RECEPTOR LOCUS (DRD2) IN ALCOHOLICS AND CONTROLS

Because of its central role in the neuromodulation of appetitive behav iors, the D-2 dopamine receptor gene (DRD2) has received considerable scrutiny as a possible candidate that may affect susceptibility to add ictive behaviors-especially alcoholism. Association studies that compa re the frequencies of anonymous restriction fragment length polymorphi sms (RFLPs) in alcoholics and controls have yielded equivocal results, suggesting that any role played by this receptor will account for onl y part of the variation. Since these RFLPs are not located in coding r egions, the hypothesis has been advanced that the association seen in some studies results from linkage disequilibrium between these markers and one or more functional DRD2 alleles that affect susceptibility. T o test this hypothesis, we have assayed four DRD2 RFLPs that span codi ng regions as well. as a 3' flanking RFLP in an expanded sample of 88 unrelated Caucasian alcoholics and 89 unrelated race-matched controls. No significant difference for any RFLP frequency between these sample s was observed, although for one marker (phD2-244), the alcoholic samp le showed a significant departure from the Hardy-Weinberg equilibrium. The pattern of pairwise composite disequilibrium coefficients is broa dly similar in the two samples, although when the five-marker haplotyp e frequencies are compared, a significant difference is revealed, This difference appears to be due to greater linkage disequilibrium of the control sample. These results do not support the involvement of the D RD2 region in the etiology of alcoholism. (C) 1994 Academic Press, Inc .