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.
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