Yamada Kazuo, Hattori Eiji, Iwayama Yoshimi, Toyota Tomoko, Iwata Yasuhide, Suzuki Katsuaki, Kikuchi Mitsuru, Hashimoto Tasuku, Kanahara Nobuhisa, Mori Norio, Yoshikawa Takeo
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.
Schizophr Res. 2015 Oct;168(1-2):444-9. doi: 10.1016/j.schres.2015.08.018. Epub 2015 Aug 29.
There is consistent data from European cohorts suggesting a genetic contribution from the major histocompatibility complex (MHC) to the pathogenesis of schizophrenia. However, the genomic complexity and ethnicity-specific diversity found in the MHC cause difficulties in identifying causal variants or genes, and there is a need for studies encompassing the entire MHC region in multiple ethnic populations. Here, we report on association signals in the MHC region, with schizophrenia in the Japanese population. We genotyped and imputed a total of 10,131 single nucleotide polymorphisms (SNPs), spanning the entire MHC interval. The analysis included 3302 participants (1518 schizophrenics and 1784 healthy controls) from the Japanese population. In this study, we present evidence for association at rs494620, located in the SLC44A4 gene. The association survived after correction for multiple testing (unadjusted P=7.78×10(-5), empirical P=0.0357). The imputation results detected the highest association at rs707937 in the MSH5-SAPCD1 gene (imputed P=8.40×10(-5)). In expression analysis using postmortem brains from schizophrenia and control samples, MSH5-SAPCD1 showed marginally significant expression differences in Brodmann's area 46 (P=0.044 by unpaired t test with Welch's correction, P=0.099 by Mann-Whitney U test). Our study further strengthens evidence for the involvement of the MHC in schizophrenia across populations, and provides insight into population-specific mechanisms for the MHC region in schizophrenia susceptibility.
来自欧洲队列的一致数据表明，主要组织相容性复合体（MHC）在精神分裂症的发病机制中存在遗传贡献。然而，MHC中发现的基因组复杂性和种族特异性多样性使得识别因果变异或基因变得困难，因此需要在多个种族人群中开展涵盖整个MHC区域的研究。在此，我们报告了日本人群中MHC区域与精神分裂症的关联信号。我们对跨越整个MHC区间的总共10131个单核苷酸多态性（SNP）进行了基因分型和推算。分析纳入了3302名日本人群参与者（1518名精神分裂症患者和1784名健康对照）。在本研究中，我们提供了位于SLC44A4基因的rs494620存在关联的证据。该关联在多重检验校正后仍然显著（未校正P = 7.78×10⁻⁵，经验性P = 0.0357）。推算结果在MSH5 - SAPCD1基因的rs707937处检测到最高关联（推算P = 8.40×10⁻⁵）。在使用精神分裂症患者和对照样本的死后大脑进行的表达分析中，MSH5 - SAPCD1在布罗德曼46区显示出边缘显著的表达差异（经韦尔奇校正的不成对t检验P = 0.044，曼 - 惠特尼U检验P = 0.099）。我们的研究进一步强化了MHC在不同人群精神分裂症中起作用的证据，并为MHC区域在精神分裂症易感性中的种族特异性机制提供了见解。
