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

Abstract

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 ¼ 330) and screened unaffected normal controls (n ¼ 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) ¼ 35%) and controls (f(Met) ¼ 27%) (p ¼ 0.004; corrected p ¼ 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 ¼ 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.

Association of p.Val158Met COMT polymorphism with paranoid ideation in drug addicts

“…These results are in accordance with the literature [20,21,31]. But other authors have not replicated these findings [18,32,33]. Therefore, there is no agreement in literature about which of the alleles increases the risk.…”

“…In fact, the most studied DA-related polymorphism in psychiatric and behavioral genetics is p.Val158Met. The PFC dysfunction might be important in drug abuse contributing to loss of control and denial [10,18]. Individual genetic differences modulating COMT activity might therefore influence the vulnerability to substance use disorders.…”

Gender‐specific COMT Val158Met polymorphism association in Spanish schizophrenic patients

“…This gender differences may reflect the mild contribution of COMT variants to the disease in females, probably due to the COMT gene downregulation that protects women against the effect of COMT variants on susceptibility to SZ and the existence of compensatory mechanisms [Harrison and Tunbridge, 2008]. A gender-specific effect of the Val158Met SNP has been also observed in other neuropsychiatric disorders such as panic disorder [Domschke et al, 2007], obsessive-compulsive disorder [Pooley et al, 2007], drug abuse [Vandenbergh et al, 1997;Lohoff et al, 2008] and alcoholism [Sery et al, 2006]. Additionally, there are evidences for a sex-specific association between SZ and genotypes in other loci [e.g., GNB1L; Williams et al, 2008].…”

Perspective: Does COMT val158met Affect Behavioral Phenotypes: Yes, No, Maybe?

“…Lohoff et al (2008) provide evidence for an association between met 158 and cocaine dependent African Americans. This is in contrast to positive associations made in methamphetamine abusers, nicotine addiction, and polysubstance abusers to the val 158 allele in previously published studies (Beuten et al, 2006;Li et al, 2004;Vandenberg et al, 1997).…”