Yukiko Tomioka1, Shusuke Numata1, Makoto Kinoshita1, Hidehiro Umehara1, Shin-Ya Watanabe1, Masahito Nakataki1, Yoshimi Iwayama1, Tomoko Toyota1, Masashi Ikeda1, Hidenaga Yamamori1, Shinji Shimodera1, Atsushi Tajima1, Ryota Hashimoto1, Nakao Iwata1, Takeo Yoshikawa1, Tetsuro Ohmori1. 1. From the Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan (Tomioka, Numata, Kinoshita, Umehara, Watanabe, Nakataki, Ohmori); the Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan (Iwayama, Toyota, Yoshikawa); the Department of Psychiatry, School of Medicine, Fujita Health University, Aichi, Japan (Ikeda, Iwata); the Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan (Yamamori, Hashimoto); the Department of Neuropsychiatry, Kochi Medical School, Kochi University, Kochi, Japan (Shimodera); the Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Ishikawa, Japan (Tajima); and the Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan (Hashimoto).
Abstract
BACKGROUND: Alterations in one-carbon metabolism have been associated with schizophrenia, and vitamin B6 is one of the key components in this pathway. METHODS: We first conducted a case-control study of serum pyridoxal levels and schizophrenia in a large Japanese cohort (n = 1276). Subsequently, we conducted a meta-analysis of association studies (n = 2125). Second, we investigated whether rs4654748, which was identified in a genome-wide association study as a vitamin B6-related single nucleotide polymorphism, was genetically implicated in patients with schizophrenia in the Japanese population (n = 10 689). Finally, we assessed the effect of serum pyridoxal levels on schizophrenia risk using a Mendelian randomization (MR) approach. RESULTS: Serum pyridoxal levels were significantly lower in patients with schizophrenia than in controls, not only in our cohort, but also in the pooled data set of the meta-analysis of association studies (standardized mean difference -0.48, 95% confidence interval [CI] -0.57 to -0.39, p = 9.8 × 10-24). We failed to find a significant association between rs4654748 and schizophrenia. Furthermore, an MR analysis failed to find a causal relationship between pyridoxal levels and schizophrenia risk (odds ratio 0.99, 95% CI 0.65-1.51, p = 0.96). LIMITATIONS: Food consumption and medications may have affected serum pyridoxal levels in our cross-sectional study. Sample size, number of instrumental variables and substantial heterogeneity among patients with schizophrenia are limitations of an MR analysis. CONCLUSION: We found decreased serum pyridoxal levels in patients with schizophrenia in this observational study. However, we failed to obtain data supporting a causal relationship between pyridoxal levels and schizophrenia risk using the MR approach.
BACKGROUND: Alterations in one-carbon metabolism have been associated with schizophrenia, and vitamin B6 is one of the key components in this pathway. METHODS: We first conducted a case-control study of serum pyridoxal levels and schizophrenia in a large Japanese cohort (n = 1276). Subsequently, we conducted a meta-analysis of association studies (n = 2125). Second, we investigated whether rs4654748, which was identified in a genome-wide association study as a vitamin B6-related single nucleotide polymorphism, was genetically implicated in patients with schizophrenia in the Japanese population (n = 10 689). Finally, we assessed the effect of serum pyridoxal levels on schizophrenia risk using a Mendelian randomization (MR) approach. RESULTS: Serum pyridoxal levels were significantly lower in patients with schizophrenia than in controls, not only in our cohort, but also in the pooled data set of the meta-analysis of association studies (standardized mean difference -0.48, 95% confidence interval [CI] -0.57 to -0.39, p = 9.8 × 10-24). We failed to find a significant association between rs4654748 and schizophrenia. Furthermore, an MR analysis failed to find a causal relationship between pyridoxal levels and schizophrenia risk (odds ratio 0.99, 95% CI 0.65-1.51, p = 0.96). LIMITATIONS: Food consumption and medications may have affected serum pyridoxal levels in our cross-sectional study. Sample size, number of instrumental variables and substantial heterogeneity among patients with schizophrenia are limitations of an MR analysis. CONCLUSION: We found decreased serum pyridoxal levels in patients with schizophrenia in this observational study. However, we failed to obtain data supporting a causal relationship between pyridoxal levels and schizophrenia risk using the MR approach.
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