Abstract
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.
Highlights
Schizophrenia is one of the most mysterious and costliest mental disorders with a lifetime risk about 1% [1, 2]
Functional annotation of associated SNPs We identified 338 susceptibility SNPs located in coding DNA sequences (CDS)
In this study, we obtained SNPs associated with schizophrenia from the current results of genome-wide association studies (GWASs) and conducted functional annotation comprehensively for all susceptibility loci
Summary
Schizophrenia is one of the most mysterious and costliest mental disorders with a lifetime risk about 1% [1, 2]. Patients with a diagnosis of schizophrenia live 12–15 years shorter than normal people, and this mortality difference increases in recent decades[1]. Published twin studies found that the heritability of schizophrenia was 73–90% and environmental influence was estimated as 3–19%2,3. Basing on the high heritability of schizophrenia, genetic susceptibility factor decipherment would lead us. Genome-wide association studies (GWASs) have identified many schizophrenia susceptibility loci. Most of the disease-associated variants locate in intronic or intergenic regions[4], which causes difficulties in clarifying their effects on diseases pathogenesis. Till the majority of functional SNPs remain unrevealed in schizophrenia studies
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