Abstract
Genome-wide association studies (GWAS) have identified more than 100 loci that show robust association with schizophrenia risk. However, due to the complexity of linkage disequilibrium and gene regulatory, it is challenging to pinpoint the causal genes at the risk loci and translate the genetic findings from GWAS into disease mechanism and clinical treatment. Here we systematically predicted the plausible candidate causal genes for schizophrenia at genome-wide level. We utilized different approaches and strategies to predict causal genes for schizophrenia, including Sherlock, SMR, DAPPLE, Prix Fixe, NetWAS, and DEPICT. By integrating the results from different prediction approaches, we identified six top candidates that represent promising causal genes for schizophrenia, including CNTN4, GATAD2A, GPM6A, MMP16, PSMA4, and TCF4. Besides, we also identified 35 additional high-confidence causal genes for schizophrenia. The identified causal genes showed distinct spatio-temporal expression patterns in developing and adult human brain. Cell-type-specific expression analysis indicated that the expression level of the predicted causal genes was significantly higher in neurons compared with oligodendrocytes and microglia (P < 0.05). We found that synaptic transmission-related genes were significantly enriched among the identified causal genes (P < 0.05), providing further support for the dysregulation of synaptic transmission in schizophrenia. Finally, we showed that the top six causal genes are dysregulated in schizophrenia cases compared with controls and knockdown of these genes impaired the proliferation of neuronal cells. Our study depicts the landscape of plausible schizophrenia causal genes for the first time. Further genetic and functional validation of these genes will provide mechanistic insights into schizophrenia pathogenesis and may facilitate to provide potential targets for future therapeutics and diagnostics.
Highlights
Schizophrenia is a severe mental disorder with complex genetic architectures[1]
We explored the functional relationships between the prioritized causal genes using functional-association network (FAN) from study of Tasan et al.[25]
Causal genes identified by Sherlock We integrated the SNP associations from schizophrenia Genome-wide association studies (GWAS) (PGC2)[2] and brain eQTL data[22] using Sherlock[23] and identified 15 potential causal genes whose expression level change may contribute to schizophrenia risk (Bonferroni corrected P < 0.05) (Supplementary Table S3)
Summary
Schizophrenia is a severe mental disorder with complex genetic architectures[1]. Recent studies have showed that different types of genetic variants (including common variants such as single nucleotide polymorphism, copy number variants, rare structural variants, de novo mutations and rare disruptive variants) are involved in the etiology of schizophrenia[2,3,4,5,6,7,8,9,10]. To identify the Several key steps are needed to elucidate the genetic and pathophysiological mechanisms of schizophrenia. The first step is to identify the genetic risk variants (or loci). The second step is to pinpoint the potential causal gene (or genes) in the identified risk loci. The third step is to investigate how the causal genes exert their effect on
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