Special Theme: Catechol-O-Methyl Transferase (COMT), Recent Findings

Neuropsychopharmacology (2008) 33, 3078–3084; doi:10.1038/npp.2008.126; published online 13 August 2008

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

Falk W Lohoff1, Andrew E Weller1, Paul J Bloch1, Aleksandra H Nall1, Thomas N Ferraro1, Kyle M Kampman2, Helen M Pettinati2, David W Oslin2, Charles A Dackis2, Charles P O'Brien2 and Wade H Berrettini1

  1. 1Department of Psychiatry, Translational Research Laboratories, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
  2. 2Department of Psychiatry, Treatment Research Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Correspondence: FW Lohoff, Department of Psychiatry, Translational Research Laboratories, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, 125 South 31st Street, Philadelphia, PA 19104, USA. Tel: +1 215 573 4582; Fax: +1 215 573 2041; E-mail: lohoff@mail.med.upenn.edu

Received 27 February 2008; Revised 19 June 2008; Accepted 15 July 2008; Published online 13 August 2008.

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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=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.

Keywords:

genetics, association study, haplotype, addiction, substance abuse

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