Early-Onset Schizophrenia: A Special Phenotype of the Disease Characterized by Increased MTHFR Polymorphisms and Aggravating Symptoms

BACKGROUND: Patients with early-onset schizophrenia usually exhibit more severe symptoms, revealing a potentially distinctive disease phenotype. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate conversion and methylation modification associated with the disease. We aimed to investigate the potential effects of MTHFR polymorphisms and related methylation patterns in patients with early-onset schizophrenia, which implies special phenotypes of schizophrenia. METHODS: In 177 patients with schizophrenia, MTHFR polymorphism at three sites (C677T, A1298C, and G1793A) and the Positive and Negative Syndrome Scale (PANSS) were tested. Differential methylation positions (DMPs) and enrichment of genes and related pathways were analyzed by testing the genomic methylation level. Catechol-O-methyltransferase (COMT), solute carrier family 6 member 4 (SLC6A4), neuregulin1 (NRG1), and brain-derived neurotrophic factor (BDNF) were selected to evaluate the methylation levels of specific CpG regions by pyrosequencing. RESULTS: Higher levels of symptom severity and MTHFR polymorphisms and lower levels of global DNA methylation in patients with early-onset schizophrenia were observed in this study. SLC6A4 was hypermethylated, and BDNF was hypomethylated in specific regions of patients with early-onset schizophrenia. CONCLUSION: Aggravating symptoms, increased MTHFR polymorphisms, and reduced genomic methylation levels may be characteristics and underlying mechanisms of early-onset schizophrenia, which implies a special disease phenotype. Beyond that, specific genes and biological pathways may imply the potential phenotype of schizophrenia.