Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population.
Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population.
复制标题
细胞粘附分子通路和NLGN1多态性与中国汉族人群精神分裂症相关的证据
DOI：
10.1371/journal.pone.0144719
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yue W
中科院分区：
文献类型：
--
作者：
Zhang Z;Yu H;Jiang S;Liao J;Lu T;Wang L;Zhang D;Yue W
全基因组关联研究（GWAS）已经确定了精神分裂症的多种风险变体。作为对GWAS的补充，已有的基于通路的分析表明细胞粘附分子（CAM）通路可能参与精神分裂症的发病。然而，较少的复制研究报告。本研究的目的是探讨中国汉族人群中CAMs通路与精神分裂症的关系。我们首先利用我们以前的GWAS数据进行了途径分析。使用基于混合基因集的检验（P = 1.03×10−10）和超几何检验（P = 5.04×10−6），CAMs通路（hsa 04514）与精神分裂症显著相关。HLA-A、HLA-C、HLA-DOB、HLA-DPB 1、HLA-DQA 2、HLA-DRB 1、MPZ、CD 276、NLGN 1、NRCAM、CLDN 1和ICAM 3等12个基因与精神分裂症有中度显著性相关（P<0.01）。然后，我们选择了一个有希望的基因神经连接素1（NLGN 1），进一步研究了8个显着的SNPs与精神分裂症的独立样本（1814例精神分裂症患者和1487名健康对照）。我们的研究表明，NLGN 1的7个SNPs和2个单倍型块与精神分裂症显著相关。综合分析的结果证实了这种关联。其中，SNP rs 9835385与精神分裂症的关联最显著（P = 2.83×10−7）。此外，在计算机模拟分析中，我们证明NLGN 1优先在人脑中表达，SNP rs 1488547与表达水平相关。我们在通路水平上验证了CAMs通路与精神分裂症的相关性，并鉴定了一个易感基因NLGN 1。CAMs通路在精神分裂症发病机制中的作用有待进一步研究。
Multiple risk variants of schizophrenia have been identified by Genome-wide association studies (GWAS). As a complement for GWAS, previous pathway-based analysis has indicated that cell adhesion molecules (CAMs) pathway might be involved in the pathogenesis of schizophrenia. However, less replication studies have been reported. Our objective was to investigate the association between CAMs pathway and schizophrenia in the Chinese Han population. We first performed a pathway analysis utilizing our previous GWAS data. The CAMs pathway (hsa04514) was significantly associated with schizophrenia using hybrid gene set-based test (P = 1.03×10−10) and hypergeometric test (P = 5.04×10−6). Moreover, 12 genes (HLA-A, HLA-C, HLA-DOB, HLA-DPB1, HLA-DQA2, HLA-DRB1, MPZ, CD276, NLGN1, NRCAM, CLDN1 and ICAM3) were modestly significantly associated with schizophrenia (P<0.01). Then, we selected one promising gene neuroligin 1 (NLGN1) to further investigate the association between eight significant SNPs and schizophrenia in an independent sample (1814 schizophrenia cases and 1487 healthy controls). Our study showed that seven SNPs of NLGN1 and two haplotype blocks were significantly associated with schizophrenia. This association was confirmed by the results of combined analysis. Among them, SNP rs9835385 had the most significant association with schizophrenia (P = 2.83×10−7). Furthermore, in silico analysis we demonstrated that NLGN1 is preferentially expressed in human brain and SNP rs1488547 was related to the expression level. We validated the association of CAMs pathway with schizophrenia in pathway-level and identified one susceptibility gene NLGN1. Further investigation of the roles of CAMs pathway in the pathogenesis of schizophrenia is warranted.