Contribution of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms to Negative Symptoms in Schizophrenia

Background: Folate deficiency may contribute to negative symptoms in schizophrenia, but the underlying mechanism remains uncertain. We examined whether the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C functional polymorphisms contribute to negative symptoms. Methods: Outpatients with schizophrenia (n = 200) were evaluated with the Positive and Negative Syndrome Scale (PANSS). Subjects also provided a blood sample for MTHFR genotype and serum chemistries. Comparisons of PANSS symptoms, folate, and homocysteine status were conducted based on genotype. Results: The 677T allele load was associated with negative symptom severity. Contrary to our expectations, the T allele was also found to be protective against positive symptoms. The A1298C polymorphism did not contribute to negative symptoms, and only weakly to positive symptoms. The specific effects of the C677T polymorphism were confirmed with haplotype analysis. Among patients homozygous for the 667T allele, serum folate levels correlated with negative symptom severity. Conclusions: Increased MTHFR 677T allele load confers risk for negative symptoms in schizophrenia, while reducing severity of positive symptoms. Further, the biochemical interaction of low serum folate with 677T-variant MTHFR may induce downstream effects salient to the expression of negative symptoms.