LINKAGE AND ASSOCIATION OF A FUNCTIONAL DRD2 VARIANT [SER311CYS] AND DRD2 MARKERS TO ALCOHOLISM, SUBSTANCE-ABUSE AND SCHIZOPHRENIA IN SOUTHWESTERN AMERICAN-INDIANS

Alcoholism is one of a group of common psychiatric diseases which are well-defined clinically and strongly influenced genetically, but which are likely to be highly heterogeneous in causation, genetically and o therwise, Dopamine is a key neurotransmitter in drug-mediated reinforc ement, Based on association studies with the Taq1A downstream marker, the D2 dopamine receptor has been proposed to be the ''Reward Deficien cy Syndrome Gene,'' Ser311Cys, a naturally occurring variant which lar gely inactivates transduction after D2 receptor activation, was abunda nt (0.16) in a Southwestern American Indian population we studied. The refore, we were able to provide a critical test of the D2 hypothesis o f vulnerability to alcoholism by evaluating Ser311Cys and also the int ron-2 STR and Taq1A markers at this locus in a total of 459 subjects, including 373 sib pairs, from large families, The result is that neith er alcoholism, substance use disorders nor schizophrenia show a relati onship to Ser311Cys genotype, even when the 15 Cys311/Cys311 homozygou s individuals are compared to others, Furthermore, sib pair analysis i ncorporating information across all three sib pair categories: concord ant affected, discordant and concordant unaffected revealed no effect of DRD2 genotype or haplotype on alcoholism or substance use disorder. (C) 1997 Wiley-Liss, Inc.