Regulation of cortical and peripheral GCH1 expression and biopterin levels in schizophrenia-spectrum disorders

Abstract

Tetrahydrobiopterin (BH₄) is an essential cofactor for dopamine, serotonin and nitric oxide synthesis. Deficits of plasma total biopterin (a measure of BH₄) have been described in schizophrenia and schizoaffective disorder. GCH1 encodes the first and rate-limiting enzyme in BH₄ synthesis. Peripheral GCH1 expression is lower in first episode psychosis patients versus controls, and we hypothesized that a GCH1 promoter polymorphism associated with psychiatric illness, contributes to regulation of both GCH1 expression and BH₄ levels. We tested this hypothesis in 120 subjects (85 patients with schizophrenia or schizoaffective disorder and 35 controls): Patients with the rs10137071 A allele had significantly lower plasma biopterin than GG patients and controls. In additional samples we assessed the relationship between genotype and diagnosis (schizophrenia or control) on GCH1 expression in the prefrontal cortex (n = 67) and peripheral leukocytes (n = 53). We found a significant linear relationship between GCH1 and study group in the CNS and periphery, with A allele patients having lower expression. Finally, in antipsychotic naïve patients (n = 13) we tested for an effect of medication on GCH1: Expression rose significantly after the onset of medication, primarily in A allele patients. These data suggest the potential for personalized genetic approaches to ameliorating BH₄ deficits in schizophrenia-spectrum disorders.

Keywords: GTP cyclohydrolase I; Gene expression; Promoter; Schizoaffective disorder; Schizophrenia; Tetrahydrobiopterin deficit.