Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects

Only in the past decade has a role of heredity in substance abuse been established as a result of extensive twin and family studies.(1,2) More recently, several candidate genes have been investigated for their possible role in alcoholism(3-6) and cocaine abuse.(7) Specific genetic factors in opioid substance abuse have not been investigated in man, although animal studies suggest that quantitative trait loci (QTLs) can be identified that predispose mice both to morphine and alcohol preference.(8) Central dopaminergic pathways figure prominently in drug-mediated reinforcement(9) suggesting that dopamine receptors are likely candidates for association with substance abuse in man. In addition, we recently reported an association between a human personality trait, Novelty Seeking(10-12) and the long alleles (represented chiefly by the 7-repeat) of the D4 dopamine receptor (D4DR) exon III polymorphism. The personality trait of Novelty Seeking is also more pronounced in substance abusers, who score higher in this dimension than control subjects.(13) The twin role of dopamine receptors in mediating Novelty Seeking(10-12) and drug-reinforcement(9) prompted us to examine a group of Israeli heroin addicts for prevalence of the D4DR repeat polymorphism. We now show that the 7-repeat allele is significantly over-represented in the opioid-dependent cohort and confers a relative risk of 2.46. To our knowledge this is the first report of an association between a specific genetic polymorphism and opioid addiction.