A Cross-Tissue Transcriptome-Wide Association Study Identifies Novel Susceptibility Genes for Glomerular Diseases

Background/Objectives: Glomerular diseases (GD) possess strong polygenic susceptibility, yet exact causal genes remain unclear because most variants identified by genome-wide association studies (GWAS) reside in non-coding regions. While transcriptome-wide association studies (TWAS) effectively decode complex traits, cross-tissue profiling for GD remains largely unexplored. Therefore, this study employs an integrative cross-tissue TWAS and Mendelian randomization framework to systematically identify and validate novel GD susceptibility genes. Methods: We conducted a systematic cross-tissue TWAS integrating Genotype-Tissue Expression (GTEx) v8 eQTL data across 49 tissues. Candidate genes were nominated using five complementary frameworks (sparse canonical correlation analysis (sCCA), functional summary-based imputation (FUSION), fine-mapping of causal gene sets (FOCUS), summary-data-based Mendelian randomization (SMR), and multi-marker analysis of genomic annotation (MAGMA)). Findings were refined via Mendelian randomization (MR), pathway enrichment, protein interaction networks, and druggability profiling. Results: We identified 21 candidate susceptibility genes for GD, with 10 genes (AGER, C6orf48, CSNK2B, CYP21A2, HLA-DRB1, HSD17B8, LST1, MICB, PRRT1, TCF19) strongly supported by MR analysis. Notably, five of these MR-prioritized genes (C6orf48, CSNK2B, HSD17B8, LST1, and PRRT1) were previously unreported. Functionally, these prioritized genes are primarily involved in immune modulation, inflammation, and steroid metabolism. Furthermore, five genes (AGER, CSNK2B, CYP21A2, HLA-DRB1 and MICB) were identified as potentially druggable targets. Conclusions: This first systematic cross-tissue TWAS of GD prioritizes a set of genetically supported susceptibility genes. By uncovering novel drivers and druggable proteins, this study advances the mechanistic understanding of GD and provides a foundation for future therapeutic development and precision nephrology.