Association Between the Catechol-O-Methyltransferase Val158Met Polymorphism and Cocaine Dependence

Dopaminergic brain systems have been documented to have a major role in drug reward, thus making genes involved in these circuits plausible candidates for susceptibility to substance use disorders. The catechol-O-methyltransferase (COMT) is involved in the degradation of catecholamines and a functional polymorphism (Val158Met) has been suggested to influence enzyme activity. In this study we hypothesize that genetic variation in the COMT gene contributes to increased risk for cocaine dependence. Cocaine-dependent individuals (n = 330) and screened unaffected normal controls (n = 255) were genotyped for three SNPs in the COMT gene ( rs737865, rs4680 (Val158Met), rs165599). All cases and controls were of African descent. Genotype and allele frequencies differed significantly for the Val158Met polymorphism between cases (f(Met) = 35%) and controls (f(Met) = 27%) (p = 0.004; corrected p = 0.014; OR 1.44; 95% CI 1.12-1.86). Haplotype analysis showed a significant association for a two-marker haplotype rs737865-Val158Met ( p = 0.005). Results suggest that variation in COMT increases risk for cocaine dependence. The low enzyme activity 158Met allele or haplotypes containing this variant might have functional effects on dopamine-derived reward processes and cortical functions resulting in increased susceptibility for cocaine dependence. Additional studies are required to elucidate the role of COMT in the pathophysiology of substance use disorders.