title: Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis.
abstract: Catechol-O-methyltransferase (COMT) has been largely studied in relation to schizophrenia susceptibility. Most studies focused on the functional single nucleotide polymorphism (SNP) rs4680 that causes a substitution of Val by Met at codon 158 of the COMT protein. Recent meta-analyses do not support an association between allelic variants at rs4680 and schizophrenia. However, the putative role of overdominance has not been tested in meta-analyses, despite its biological plausibility. In this work, we tested the overdominant model in two Spanish samples (from Valencia and Santiago de Compostela), representing a total of 762 schizophrenic patients and 1042 controls, and performed a meta-analysis of the available studies under this model. A total of 51 studies comprising 13,894 schizophrenic patients and 16,087 controls were included in the meta-analysis, that revealed a small but significant protective effect for heterozygosity at rs4680 (pooled OR=0.947, P=0.023). Post-hoc analysis on southwestern European samples suggested a stronger effect in these populations (pooled OR=0.813, P=0.0009). Thus, the COMT functional polymorphism rs4680 contributes to schizophrenia genetic susceptibility under an overdominant model, indicating that both too high and too low levels of dopamine (DA) signalling may be risk factors. This effect can be modulated by genetic background.
authors.affiliation: Fundación Pública Galega de Medicina Xenómica-SERGAS, Complexo Hospitalario Universitario de Santiago, Edif. Consultas Planta 2, E-15706 Santiago de Compostela, Spain. javier.costas@usc.es
authors.forename: Javier
authors.initials: J
authors.lastname: Costas
authors.forename: Julio
authors.initials: J
authors.lastname: Sanjuán
authors.forename: Ramón
authors.initials: R
authors.lastname: Ramos-Ríos
authors.forename: Eduardo
authors.initials: E
authors.lastname: Paz
authors.forename: Santiago
authors.initials: S
authors.lastname: Agra
authors.forename: José Luis
authors.initials: JL
authors.lastname: Ivorra
authors.forename: Mario
authors.initials: M
authors.lastname: Páramo
authors.forename: Julio
authors.initials: J
authors.lastname: Brenlla
authors.forename: Manuel
authors.initials: M
authors.lastname: Arrojo
mesh_terms: D002394:Catechol O-Methyltransferase / Q000235:genetics*; D016001:Confidence Intervals; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008715:Methionine / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D014633:Valine / Q000235:genetics*
chemical_list: D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine