A FUNCTIONALLY DEFICIENT DRD2 VARIANT [SER311CYS] IS NOT LINKED TO ALCOHOLISM AND SUBSTANCE-ABUSE

Association studies with the DRD2 Taq1A marker have been variable in i mplicating DRD2 as a ''Reward Deficiency Syndrome Gene'' for alcoholis m and substance abuse. Given that the Taq1A marker is not functionally significant, second-generation studies on the DRD2 receptor to identi fy functional variants and evaluate their effect on the phenotype are the logical step towards confirming and extending the DRD2 hypothesis. This article discusses the implications and process of progress made in these directions. The new findings are the description of structura l variants in the D-2 receptor, the demonstration that one of these, S er311Cys, largely prevents signal transduction following receptor acti vation and the use of Ser311Cys in a large association and sib-pair li nkage anlysis in an American Indian isolate. In this particular popula tion, the Cys311 variant is far more abundant (0.16) than in Caucasian s (0.03). Genotyping of Ser311Cys, the DRD2 intron 2 STR, and the Taq1 A marker in 459 subjects, including 373 sib-pairs and 15 Cys311/Cys311 homozygous individuals, revealed no association to alcoholism, substa nce use disorders, or schizophrenia. The implication is that a DRD2 va riant that dramatically impairs receptor function was not sufficient t o significantly alter alcoholism vulnerability in a relatively large a nd also genetically and environmentally homogeneous sample. Published by Elsevier Science Inc.