J Psychiatry Neurosci 2018;43(3):194-200
Yukiko Tomioka, MD; Shusuke Numata, MD, PhD; Makoto Kinoshita, MD, PhD; Hidehiro Umehara, MD, PhD; Shin-ya Watanabe, MD, PhD; Masahito Nakataki, MD, PhD; Yoshimi Iwayama, MS; Tomoko Toyota, MD, PhD; Masashi Ikeda, MD, PhD; Hidenaga Yamamori, MD, PhD; Shinji Shimodera, MD, PhD; Atsushi Tajima, PhD; Ryota Hashimoto, MD, PhD; Nakao Iwata, MD, PhD; Takeo Yoshikawa, MD, PhD; Tetsuro Ohmori, MD, PhD
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.
Submitted Mar. 9, 2017; Revised Aug. 21, 2017; Revised Oct. 17, 2017; Accepted Oct. 22, 2017; Published online first Feb. 6, 2018
Acknowledgements: The authors thank all of the volunteers who participated in this study as well as the physicians who helped collect clinical data and blood samples at the mental hospitals. The authors also thank Akemi Okada for her technical assistance and Tetsuo Ohnishi for his help for genotype analysis.
Affiliations: 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).
Funding: This work was supported in part by the Japan Agency for Medical Research and Development, AMED (T.O.), Grant-in-Aid for Scientific Research (C) (No.15K09809) (S.N.), and Grant-in-Aid for Young Scientists (B) (No.16K19768) (M.K.), and the grant from Research Group for Schizophrenia (S.N.), and the grant from SENSHIN Medical Research Foundation (M.K.).
Competing interests: None declared.
Contributors: S. Numata and T. Ohmori designed the study. Y. Tomioka, M. Kinoshita, H. Umehara, S. Watanabe, Y. Iwayama, T. Toyota, M. Ikeda, S. Shimodera and N. Iwata acquired the data, which Y. Tomioka, S. Numata, M. Kinoshita, M. Nakataki, H. Yamamori, A. Tajima, R. Hashimoto and T. Yoshikawa analyzed. Y. Tomioka and S. Numata wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Correspondence to: S. Numata, Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15 Kuramoto-cho Tokushima 770-8503, Japan; firstname.lastname@example.org