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Comprehensive functional annotation of susceptibility SNPs prioritized 10 genes for schizophrenia

机译:综合功能注释的易感性SNPs优先为精神分裂症的10个基因

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摘要

Nearly 95% of susceptibility SNPs identified by genome-wide association studies (GWASs) are located in non-coding regions, which causes a lot of difficulty in deciphering their biological functions on disease pathogenesis. Here, we aimed to conduct a comprehensive functional annotation for all the schizophrenia susceptibility loci obtained from GWASs. Considering varieties of epigenomic regulatory elements, we annotated all 22,688 acquired susceptibility SNPs according to their genomic positions to obtain functional SNPs. The comprehensive annotation indicated that these functional SNPs are broadly involved in diverse biological processes. Histone modification enrichment showed that H3K27ac, H3K36me3, H3K4me1, and H3K4me3 were related to the development of schizophrenia. Transcription factors (TFs) prediction, methylation quantitative trait loci (meQTL) analyses, expression quantitative trait loci (eQTL) analyses, and proteomic quantitative trait loci analyses (pQTL) identified 447 target protein-coding genes. Subsequently, differential expression analyses between schizophrenia cases and controls, nervous system phenotypes from mouse models, and protein–protein interaction with known schizophrenia-related pathways and genes were carried out with our target genes. We finaly prioritized 10 target genes for schizophrenia (CACNA1C, CLU, CSNK2B, GABBR1, GRIN2A, MAPK3, NOTCH4, SRR, TNF, and SYNGAP1). Our results may serve as an encyclopedia of schizophrenia susceptibility SNPs and offer holistic guides for post-GWAS functional experiments.
机译:通过全基因组关联研究(GWAS)鉴定出的易感性SNP中,有近95%位于非编码区,这在解释其在疾病发病机理上的生物学功能时会遇到很多困难。在这里,我们旨在对从GWAS获得的所有精神分裂症易感基因座进行全面的功能注释。考虑到各种表观基因调控元件,我们根据其基因组位置标注了所有22,688个获得的易感性SNP,以获得功能性SNP。全面的注释表明,这些功能性SNP广泛参与各种生物过程。组蛋白修饰富集表明H3K27ac,H3K36me3,H3K4me1和H3K4me3与精神分裂症的发生有关。转录因子(TFs)预测,甲基化定量特征基因座(meQTL)分析,表达定量特征基因座(eQTL)分析和蛋白质组学定量特征基因座分析(pQTL)确定了447个目标蛋白质编码基因。随后,用我们的靶基因进行了精神分裂症病例与对照,小鼠模型的神经系统表型以及与已知精神分裂症相关途径和基因的蛋白质相互作用的差异表达分析。我们最终确定了精神分裂症的10个靶基因的优先级(CACNA1C,CLU,CSNK2B,GABBR1,GRIN2A,MAPK3,NOTCH4,SRR,TNF和SYNGAP1)。我们的结果可作为精神分裂症易感性SNP的百科全书,并为GWAS后功能实验提供整体指导。

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