Cell type-specific and cross-population polygenic risk score analyses of MIR137 gene pathway in schizophrenia

Cell type-specific pathway-based polygenic risk scores (PRSs) may better inform disease biology and improve the precision of PRS-based clinical prediction. For microRNA-137 (MIR137), a leading neuropsychiatric risk gene and a post-transcriptional master regulator, we conducted a cell type-specific gene set PRS analysis in both European and Han Chinese schizophrenia (SZ) samples. We found that the PRS of neuronal MIR137-target genes better explains SZ risk than PRS derived from MIR137-target genes in iPSC or from the reported gene sets showing MIR137-altered expression. Compared with the PRS derived from the whole genome or the target genes of TCF4, the PRS of neuronal MIR137-target genes explained a disproportionally larger (relative to SNP number) SZ risk in the European sample, but with a more modest advantage in the Han Chinese sample. Our study demonstrated a cell type-specific polygenic contribution of MIR137-target genes to SZ risk, highlighting the value of cell type-specific pathway-based PRS analysis for uncovering disease-relevant biological features.