Department of Social Medicine; University of Bristol
Gene expression patterns, which are largely controlled by epigenetic mechanisms such as DNA methylation, have been shown to be altered for a number of genes in patients with schizophrenia. Aberrant methylation of DNA early in life could lead to abnormal neurodevelopment and may be important in the etiology of schizophrenia. Genetic factors, along with environmental exposures, such as maternal dietary folate intake determine fetal methylation levels. However, observational studies, which show associations of folate intake during pregnancy and subsequent offspring schizophrenia risk are subject to bias and confounding by lifestyle and socio-economic factors, whereas associations between genetic polymorphisms and schizophrenia risk are not. The MTHFR gene C677T polymorphism influences folate metabolism and intracellular availability of folate metabolites for methylation. Individuals carrying the TT genotype have less folate available for methylation than CC homozygotes. This genotype thus serves as a marker for exposure to dietary folate. We carried out a meta-analysis of 6 studies which reported on MTHFR C677T genotype among patients with schizophrenia and controls and found that TT homozygotes had a significantly increased risk, OR 1.48(1.18-1.86). An updated meta-analysis which included 3 more studies confirms this association (Muntjewerff et al, 2005), and supports the hypothesis that folate status is a determinant of schizophrenia risk. We are currently analysing MTHFR genotype data in trios of patients with schizophrenia and their parents from Bulgaria (number of trios=651), China (n=267), and the USA (n=187) to determine whether there is an effect of maternal genotype on risk. Preliminary analysis from this study will be presented.