Schizophrenia is a debilitating disorder with a prevalence of approximately 0.5%-1% within any given population. The pathophysiology of schizophrenia involves complex genetic, environmental, and psychological etiologies. Here we summarize 26 years of research completed by the Juntendo University Schizophrenia Projects study group on the “biopsychosocial model” of schizophrenia. Clinical brain morphological abnormalities in schizophrenia were detected with magnetic resonance imaging, and these findings led to gene expression analyses of neurotransmitters. The familial aggregation pattern in schizophrenia led to the completion of genetic studies, including linkage and genome-wide analyses, and studies on environmental factors, such as nutrition, aging, stress, and inflammation. Furthermore, we developed a collaborative multicenter study that consisted of a large number of samples. This study enabled us to clearly identify the relevant pathophysiology of schizophrenia, including genetics, altered neurotransmission, brain morphology, and clinical features.
Purpose: Oxidative stress contributes to the development of schizophrenia and metabolic abnormalities among schizophrenia patients. This study investigated whether the oxidative stress-related genes polymorphisms affected the risk for metabolic abnormalities among schizophrenia patients or not.
Methods: A cross-sectional analysis was conducted among 256 schizophrenia patients and 194 age- and gender-matched controls. The effects of the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) (rs1801133, C677T; rs1801131, A1298C) and glutathione S-transferase (GST) T1 null, GSTM1 null, GSTK1 (rs1917760, G-1308T) on the risk for metabolic abnormalities were investigated by structural equation modeling.
Results: Among the female schizophrenia patients, the MTHFR rs1801133 T/T genotype increased the risk of overweight, and this genotype effect was associated with a risk of metabolic abnormalities. Among the schizophrenia patients with current-smoking status, the MTHFR rs1801133 T/T genotype also increased the risk of overweight, thus affecting the risk of metabolic abnormalities. The effects of GSTK1 T allele carriers and GSTM1 null genotypes on the increased risk of overweight were confirmed in the male schizophrenia patients and/or the patients with current-smoking status. In contrast, no association between the polymorphisms and risk of metabolic abnormalities was observed in control subjects.
Discussion: These findings suggest that the polymorphisms of oxidative stress-related genes, including MTHFR, may be a significant risk factor for overweight-related metabolic abnormalities among schizophrenia patients in relation to gender differences and/or smoking status. This information regarding the effect of high-risk genotypes may be used to prevent overweight and metabolic abnormalities.