Fig. 1

Prioritization and identification of regulatory single-nucleotide polymorphisms (SNPs) at schizophrenia risk loci. Risk SNPs (including credible causal SNPs and SNPs that were in linkage disequilibrium (LD) with the index risk SNPs) from three large-scale genome-wide association studies (GWASs) were subjected to functional annotation and functional genomics analyses. Five annotation methods were used to prioritize the most possible functional (or causal) SNPs (i.e., SNPs with the largest scores (CADD, Eigen, LINSIGHT and GWAVA) or the lowest rankings (1a, RegulomeDB)). The most possible functional SNPs (we call these SNPs top functional SNPs) were further distilled and the same top functional SNP prioritized by at least two different annotation approaches was subjected to expression quantitative loci (eQTL) annotation and reporter gene assays. We also utilized functional genomics to identify the potential causal SNPs at the risk loci. Chromatin immunoprecipitation and sequencing (ChIP-Seq) experiments performed in brain tissues or neuronal cell lines were used to identify the motifs (i.e., position weight matrices (PWMs) of corresponding transcription factors (TFs)). The identified PWMs from ChIP-Seq experiments and PWM database were compared, and the matched PWMs were used to map if the risk SNPs were located in the identified PWMs. Reporter gene assays were used to validate the effects of the identified TF binding–disrupting SNPs and eQTL annotation was performed to identify the potential target genes of the identified regulatory SNPs. The results of this study can be accessed and visualized at SZDB database (http://www.szdb.org/)