A COMT gene haplotype associated with methamphetamine abuse

INTRODUCTIONMethamphetamine (MAMP) use is highly associated with psychiatric disorders with 12–13% of MAMP-dependent patients experiencing psychotic symptoms. Substance abuse and dependence may primarily involve the mesolimbic pathway and dopaminergic brain structures. It follows that dopaminergic genes, particularly COMT (encoding catechol-O-methyltransferase) and its val158met polymorphism (rs4680), are natural candidates for susceptibility loci to addiction. We have previously found an association with rs4680 and MAMP addiction. METHODSWe present additional genotyping of rs165599 in 423 cases and 502 controls of a Taiwanese MAMP user sample. We carried out an in-silico evaluation of rs165599 for a possible impact on microRNA binding or UTR stability. We also carried out a review of transcript sequences across the COMT 3′UTR. RESULTSGenotype counts were (cases/controls)AA 94/110, AG 198/210 and GG 93/109. There were no significant allele or genotype differences between cases and controls for rs165599. However, a haplotype main effect was detected using both rs4680 and rs165599 using the χ-test in UNPHASED. The global P-value was P=0.0044 with the effect appearing to derive from one haplotype that is underrepresented in casesA/G for rs4680/rs165599 (haplotype P=0.001). rs165599 is a single nucleotide polymorphism located in the COMT 3′ untranslated region (UTR), a noncoding transcript region subject to posttranscriptional down-regulation by mechanisms such as microRNA binding. A review of transcript sequences across the COMT 3′UTR found evidence to suggest antisense interference of COMT from the 3′UTR of the neighbouring ‘Armadillo repeat gene deleted in velocardiofacial syndrome’ gene.