Homocysteine metabolism and risk of schizophrenia

Abstract

The one-carbon cycle hypothesis initiated research of schizophrenia risk in relation to sensitive markers of aberrant homocysteine metabolism, such as B-vitamin concentrations, plasma total homocysteine (tHcy) concentrations, and genetic determinants. We observed decreased plasma and elevated RBC folate levels as risk factors for schizophrenia, which appeared to be independent of tHcy concentrations (chapter 2). No deficiencies of vitamin B6 or vitamin B12 levels were found in our study. In a review we only found 7 case-control studies with data on folate levels in schizophrenia patients (chapter 3). These studies showed no substantial support for an aberrant folate metabolism in schizophrenia patients. However, all studies showed a variety of methodological flaws defying a more definite conclusion on the relationship between folate and schizophrenia. The results of a meta-analysis of the current literature (chapter 5) give support to the conclusion presented in our previous report (chapter 4) that elevated tHcy concentration is a risk factor for schizophrenia. We found that a 5 μmol/L higher tHcy concentration was associated with an increased risk of schizophrenia (OR=1.70 [95% CI: 1.27-2.29]). Next to the MTHFR 677TT genotype, we found elevated tHcy concentrations in schizophrenia patients with the heterozygous MTHFR 677C>T genotype compared to patients homozygous for the normal genotype (chapter 4). The MTHFR 677CT genotype itself may result in elevated tHcy concentrations. The results of our initial study showed no increased frequency of the 677TT genotype in schizophrenia patients (chapter 2). However, an enlargement of this initial study showed a nearly significant increased risk (OR=1.6 [95% CI: 0.96-2.8]) of schizophrenia associated with the 677TT genotype in the MTHFR gene (chapter 4). When these data were incorporated in a meta-analysis based on published studies the MTHFR 677C>T mutation in homozygous state appeared to be a significant genetic risk factor for schizophrenia with a pooled risk estimate of 1.36 (95% CI: 1.07-1.72) (chapter 5). We observed no transmission distortion of the 677T allele in 120 families with schizophrenia offspring, which is in accordance with the result of a meta-analysis using data from three family-based studies, including our data (chapter 6). When we applied a log-linear model to the case-parent data no evidence for a strong maternal genetic effect on schizophrenia risk was observed. In chapter 7 the effect of genetic variations of two interconnected enzymes of the methylation pathway, COMT and MTHFR, on schizophrenia risk were subject of study. Despite the low numbers of subjects carrying the combination of the COMT 324AA and MTHFR 677TT genotype an increased risk of schizophrenia was associated with this compound genotype in our study. Four polymorphisms of the COMT gene, and their effect on tHcy levels in population-based controls were examined (chapter 8). Only the COMT 324G>A variant was associated with homocysteine, although the effect of this polymorphism on tHcy concentration is lower than that of the MTHFR 677C>T polymorphism.