Meta-analysis of association between genetic variants in COMT and schizophrenia: An update

A common functional polymorphism, Val108/158Met (rs4680), and haplotypes rs737865–rs4680–rs165599 in the Catechol-O-methyltransferase gene (COMT) have been extensively examined for association to schizophrenia; however, results of replication studies have been inconsistent. The aim of this study was to comprehensively evaluate the genetic risk of COMT for schizophrenia.First, we performed a mutation scan to detect the existence of potent functional variants in the 5′-flanking and exon regions. Second, we conducted a gene-based case–control study between tagging single nucleotide polymorphisms (SNPs) in COMT [19 SNPs including six possible functional SNPs (rs2075507, rs737865, rs4680, rs165599, rs165849)] and schizophrenia in large Japanese samples (schizophrenics 1118, controls 1100). Lastly, we carried out a meta-analysis of 5 functional SNPs and haplotypes (rs737865–rs4680–rs165599).No novel functional variant was detected in the mutation scan. There is no association between these tagging SNPs in COMT and Japanese schizophrenia. In this updated meta-analysis, no evidence was found for an association between Val108/158Met polymorphisms, rs6267, rs165599, and haplotypes (rs7378655–rs4680–rs165599) and schizophrenia, although rs2075507 and rs737865 showed trends for significance in allele-wise analyses (P = 0.039 in a multiplicative model, P = 0.025 in a recessive model for rs2075507, P = 0.018 in a dominant model for rs737865, uncorrected). This significance did not remain, however, after correcting the P-values using a false discovery rate controlling procedure.Our results suggest that the COMT is unlikely to contribute to susceptibility to schizophrenia.