Nishi Akira, Numata Shusuke, Tajima Atsushi, Kinoshita Makoto, Kikuchi Kumiko, Shimodera Shinji, Tomotake Masahito, Ohi Kazutaka, Hashimoto Ryota, Imoto Issei, Takeda Masatoshi, Ohmori Tetsuro
Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan;
Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan;
Schizophr Bull. 2014 Sep;40(5):1154-63. doi: 10.1093/schbul/sbt154. Epub 2014 Feb 17.
Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia.
以往研究表明，血液中同型半胱氨酸水平升高以及亚甲基四氢叶酸还原酶（MTHFR）C677T基因多态性是精神分裂症的危险因素。然而，性别和MTHFR C677T基因分型对精神分裂症患者血液同型半胱氨酸水平的影响并不一致。我们首先在一个大型队列（N = 1379）中，按性别和MTHFR C677T基因分型进行分层，调查精神分裂症患者的血浆总同型半胱氨酸水平是否高于对照组。其次，我们分别按性别（N = 4714）对血液同型半胱氨酸水平与精神分裂症之间的关联研究进行了荟萃分析。第三，我们对MTHFR C677T基因多态性与精神分裂症进行了病例对照关联研究（N = 4998），并基于日本受试者（N = 10378）对基因关联研究进行了荟萃分析。最后，我们通过孟德尔随机化方法评估血浆总同型半胱氨酸水平对精神分裂症的影响。年龄校正后的协方差分析表明，在所有分层中，诊断对血浆总同型半胱氨酸水平有显著影响，随后按性别进行的荟萃分析表明，尽管抗精神病药物可能影响结果，但精神分裂症男性和女性患者的血液同型半胱氨酸水平均升高。对日本基因关联研究的荟萃分析表明，MTHFR C677T基因多态性与精神分裂症之间存在显著关联。在日本人群中进行的孟德尔随机化分析得出，血浆总同型半胱氨酸每增加1个标准差，患精神分裂症的比值比为1.15。我们的研究表明，血浆总同型半胱氨酸水平升高可能与精神分裂症风险增加有关。
