Abstract
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.
Highlights
Schizophrenia is a server and complex psychiatric disorder with an estimated worldwidepooled prevalence of 1%, characterized by hallucinations, delusions, disturbed emotions and social withdrawal [1, 2]
Single Nucleotide Polymorphism (SNP) quality control was based on the following criteria: we removed SNPs with call rates less than 90%, SNPs with minor allele frequency (MAF) less than 5%, and SNPs with significant deviation from Hardy-Weinberg equilibrium (HWE) in controls (P
To test whether cell adhesion molecules (CAMs) pathway was critical to schizophrenia, we conducted a pathway analysis using our previous Genome-wide association studies (GWAS) data with KGG software
Summary
Schizophrenia is a server and complex psychiatric disorder with an estimated worldwidepooled prevalence of 1%, characterized by hallucinations, delusions, disturbed emotions and social withdrawal [1, 2]. Decades of research for the biological pathogenesis of schizophrenia still did not completely elucidate the clearly causes of this disorder. Given its high heritability of over 80% [3], exploration of genetic mechanisms involved in schizophrenia has been attracted more and more attention [4]. Recent researches have considerably advanced our understanding in terms of identifying risk loci and the mechanisms by which genetic risk is conferred [5, 6]. Genome-wide association studies (GWAS) have identified some promising candidate genes association with schizophrenia, such as DRD2, TCF4, NOTCH4, CACNA1C and ZNF804A [7,8,9,10]. The evidence of involvement of specific genes and variants remained elusive
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