Association between the methylenetetrahydrofolate reductase 677C -> T missense mutation and schizophrenia

The schizophrenia phenotype is heterogeneous with respect to clinical prese ntation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes.' Compared to non-responders, schizophrenic patients who are responders to neuroleptic me dications are characterized by a high female/male ratio,(2) a better longte rm outcome(3) and more frequently disturbed dopamine neurotransmission.(4) In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responder s and non-responders) and a group of healthy volunteers, with regard to a m issense mutation (677C --> T) in the methylenetetrahydrofolate reductase (M THFR) gene. This polymorphism was chosen because it is functional(5) and wa s previously associated with schizophrenia.(6) The present study revealed a significant association between schizophrenia and allele T of this gene. T his association was entirely due to an over-representation of allele T in r esponder patients compared to controls; nonresponder patients did not diffe r from controls. Genotype TT was more frequent in responder patients compar ed to controls, thus replicating the findings of Arinami et al.(6) These re sults strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic respons e to typical neuroleptics and/or a good long-term prognosis/favorable thera peutic outcome.