Association analysis of the HLA-DRB1*01 and HLA-DRB1*04 with schizophrenia by tag SNP genotyping in the Japanese population.
Association analysis of the HLA-DRB1*01 and HLA-DRB1*04 with schizophrenia by tag SNP genotyping in the Japanese population.
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通过标签 SNP 基因分型在日本人群中进行 HLA-DRB1*01 和 HLA-DRB1*04 与精神分裂症的关联分析。
DOI：
10.1016/j.psychres.2015.07.016
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Hishimoto A.
中科院分区：
文献类型：
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作者：
Ratta-apha W;Boku S;Mouri K;Okazaki S;Otsuka I;Watanabe Y;Nunokawa A;Someya T;Shirakawa O;Sora I;Hishimoto A.
最近的大规模全基因组关联研究已经证明了大量与精神分裂症相关的等位基因，包括免疫系统相关基因（精神病基因组学联盟精神分裂症工作组，2014）。人类白细胞抗原（HLA）区，又称主要组织相容性复合体（MHC），是免疫系统中的重要组成部分。提示HLA等位基因可能与精神分裂症有关。实际上，标记与染色体6p 21上的MHC区域重叠。3-22.1与精神分裂症密切相关（Shi等人，2009年）。此外，de Bakker et al.（2006）定义了一个高分辨率的HLA和SNP单倍型图谱，该图谱捕获了MHC区域中的许多常见变异。除了这些西方研究之外，先前的报道发现在日本精神分裂症患者中HLA-DRB 1 * 0101（或HLA-DR 1）的频率较高，而HLA-DRB 1 * 04的频率较低（Akaho et al.，2000年，Arinami等人，1998年）。然而，在日本精神分裂症患者中的这种先前HLA研究的样本量不足以保证HLA等位基因与精神分裂症之间的关联; 45名精神分裂症患者和117名对照（Akaho等人，2000）、266名精神分裂症患者和283名对照（Arinami等人，1998年）。因此，在这里，我们研究了HLA-DRB 1 * 0101和HLA-DRB 1 * 04（* 0401，* 0403，* 0405和 * 0406）等位基因与精神分裂症之间的关联，使用标签SNP，如de Bakker et al.（2006），因为他们的方法促进了标签SNP的选择以捕获HLA变异，使得能够通过在大样本中进行关联研究来提供经典HLA分型的方法的成本有效的方法（de Bakker et al.，2006年）。所选HLA等位基因的标签SNPs信息，包括r 2和D prime在补充资料中显示。本研究得到了科比大学医学研究生院遗传学研究伦理委员会的批准。获得所有参与者的知情同意书。本研究共招募了650名无关的精神分裂症受试者（平均年龄53.4±14.6岁：345名男性和305名女性）和760名健康对照者（对照组：平均年龄54.1±18.6岁：360名男性和400名女性）。两组之间的年龄分布无显著差异（t=-0.776，df= 1408，p= 0.438）。用TaqMan探针测定（Applied Biosystems，Foster City，CA，USA）对所有选择的SNP标记进行基因分型。用χ 2检验确定等位基因关联。如所述通过使用Nyholt方法（Nyholt，2004）对LD中所选标签SNP的多重测试进行校正。统计学显著性定义为p< 0.05。
Recent large-scale genome-wide association studies have demonstrated a large number of alleles associated with schizophrenia, including immune system-related genes (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). Human leukocyte antigen (HLA) region, also called the major histocompatibility complex (MHC), is well known to play an essential role in immune system. These suggest that HLA alleles might be associated with schizophrenia. Actually, the markers overlapping with MHC region on chromosome 6p21. 3–22.1 are strongly associated with schizophrenia (Shi et al., 2009). Moreover, de Bakker et al.(2006) defined a high-resolution HLA and SNP haplotype map that captures much of the common variation in the MHC region. In addition to these Western studies, previous reports found a higher frequency of HLA-DRB1* 0101 (or HLA-DR1) and a lower frequency of HLA-DRB1* 04 in Japanese schizophrenic patients (Akaho et al., 2000, Arinami et al., 1998). However, such previous HLA studies in Japanese schizophrenia patients had inadequate sample size to warrant the association between HLA alleles and schizophrenia; 45 schizophrenic patients and 117 controls (Akaho et al., 2000), 266 schizophrenic patients and 283 controls (Arinami et al., 1998). Therefore, here we investigated the association between HLA-DRB1* 0101 and HLA-DRB1* 04 (* 0401,* 0403,* 0405 and* 0406) alleles and schizophrenia using tag SNPs as described in de Bakker et al.(2006), because their method facilitated the selection of tag SNPs to capture HLA variation, enabling a cost-effective method for providing an approach to classical HLA typing by conducting association studies in large samples (de Bakker et al., 2006). The selected HLA alleles' tag SNPs information, including r 2 and D prime are shown in supplementary materials.The present study was approved by the ethical committee for genetic studies of Kobe University Graduate School of Medicine. Informed consent was obtained from all participants. A total of 650 unrelated schizophrenic subjects (mean age 53.4±14.6 years: 345 males and 305 females) and 760 healthy controls (controls: mean age 54.1±18.6 years: 360 males and 400 females) were recruited for the present study. There were no significant differences in age distribution between two groups (t=− 0.776, df= 1408, p= 0.438). All of the selected SNP markers were genotyped with TaqMan probe assays (Applied Biosystems, Foster City, CA, USA). Allelic association was determined using χ 2 test. Correction for multiple testing for selected tag SNPs in LD was applied as described by using the Nyholt method (Nyholt, 2004). Statistical significance was defined at p< 0.05.