Cell Type-Specific and Cross-Population Polygenic Risk Score Analyses of <i>MIR137</i> Gene Pathway in Schizophrenia

Abstract

Cell-type-specific pathway-based polygenic risk scores (PRS) may better inform disease biology and improve the precision and cross-ethnicity portability of PRS-based clinical prediction. Here, for microRNA-137 (MIR137), a leading neuropsychiatric risk gene and a posttranscriptional master regulator, we conducted a cell-type-specific gene set-based PRS analysis in both European and Han Chinese schizophrenia (SZ) samples. We found that the PRS of neuronal MIR137 target genes better explains the SZ risk variance, with PRS in glutamatergic neurons showing the best performance. Compared to the PRS derived from the whole genome or the target genes of a transcriptional master regulator TCF4, the PRS of neuronal MIR137 target genes explained a disproportionally larger SZ risk variance in both European and Han Chinese samples. Our study demonstrated a substantial cell-type-specific polygenic contribution of MIR137 target genes to SZ risk variance across ethnicity, highlighting the value of cell-type-specific pathway-based PRS analysis for uncovering disease-relevant biological features.