Association Study of Nogo-Related Genes With Schizophrenia in a Japanese Case-Control Sample
Association Study of Nogo-Related Genes With Schizophrenia in a Japanese Case-Control Sample
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DOI：
10.1002/ajmg.b.31199
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发表时间：
2011-07-01
影响因子：
2.8
通讯作者：
Yoshikawa, Takeo
中科院分区：
文献类型：
--
作者：
Jitoku, Daisuke;Hattori, Eiji;Yoshikawa, Takeo
许多研究表明，髓鞘功能障碍可能与精神分裂症的发病机制有因果关系。Nogo（RTN 4）、髓鞘相关糖蛋白（MAG）和少突胶质细胞髓鞘糖蛋白（OMG）都与共同受体Nogo-66受体1（RTN 4 R）结合。我们使用来自日本人群的2，120例病例对照样本，检测了来自这四个基因的68个单核苷酸多态性（SNPs）（51个基因分型，17个插补分析）与精神分裂症的遗传关联。等位基因测试显示，两个RTN 4 SNP（rs 11894868和rs 2968804分别为P = 0.047和0.037）和两个MAG SNP（rs7249617和rs 16970218分别为P = 0.034和0.029）与精神分裂症存在名义上显著的相关性。MAG SNP rs7249617在基因型检验中也显示名义显著性（P = 0.017）。在单倍型分析中，包括rs7249617和rs 16970218的MAG单倍型块显示名义上的显著性（P = 0.008）。这些关联在多次测试校正后并不显著，可能是由于它们的遗传效应很小。在RTN 4的插补分析中，未分型的SNP rs 2972090显示出名义上显着的关联（P = 0.032），而几个插补的SNP显示出边缘关联。此外，在计算机分析（PolyPhen）的错义变体（rs 11677099：Asp 357 Val），这是在强烈的连锁不平衡与rs 11894868，预测Nogo蛋白功能的有害影响。尽管未能在这个日本队列中检测到强有力的关联，但我们名义上的阳性信号，加上以前报道的生物学和遗传学发现，进一步支持了不同人群中的“精神分裂症髓鞘系统紊乱理论”。(C)2011 Wiley-Liss，Inc.
Many studies have suggested that myelin dysfunction may be causally involved in the pathogenesis of schizophrenia. Nogo (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG) all bind to the common receptor, Nogo-66 receptor 1 (RTN4R). We examined 68 single nucleotide polymorphisms (SNPs) (51 with genotyping and 17 with imputation analysis) from these four genes for genetic association with schizophrenia, using a 2,120 case-control sample from the Japanese population. Allelic tests showed nominally significant association of two RTN4 SNPs (P = 0.047 and 0.037 for rs11894868 and rs2968804, respectively) and two MAG SNPs (P = 0.034 and 0.029 for rs7249617 and rs16970218, respectively) with schizophrenia. The MAG SNP rs7249617 also showed nominal significance in a genotypic test (P = 0.017). In haplotype analysis, the MAG haplotype block including rs7249617 and rs16970218 showed nominal significance (P = 0.008). These associations did not remain significant after correction for multiple testing, possibly due to their small genetic effect. In the imputation analysis of RTN4, the untyped SNP rs2972090 showed nominally significant association (P = 0.032) and several imputed SNPs showed marginal associations. Moreover, in silico analysis (PolyPhen) of a missense variant (rs11677099: Asp357Val), which is in strong linkage disequilibrium with rs11894868, predicted a deleterious effect on Nogo protein function. Despite a failure to detect robust associations in this Japanese cohort, our nominally positive signals, taken together with previously reported biological and genetic findings, add further support to the "disturbed myelin system theory of schizophrenia" across different populations. (C) 2011 Wiley-Liss, Inc.