Systematic prioritization of potential therapeutic targets for glomerulonephritis using multi-omics Mendelian randomization

Glomerulonephritis (GN) is an immune-mediated kidney disorder that causes glomerular injury, progressive renal dysfunction, and end-stage kidney disease. Traditional treatments such as corticosteroids and immunosuppressants are limited by variable efficacy and severe adverse effects, highlighting the need for novel therapeutic targets and personalized strategies. We performed a systematic multi-omics Mendelian randomization (MR) analysis applying established proteomic and transcriptomic quantitative trait loci (pQTL/eQTL) resources to genome-wide association studies (GWAS) of four GN subtypes: acute, chronic, IgA nephropathy, and membranous nephropathy. Bayesian colocalization was used to strengthen causal inference, while independent replication and meta-analysis were conducted using the FinnGen cohort. Mouse knockout phenotypes, drug reposition, and computational pharmacology algorithm were applied to evaluate translational potential. Proteomic-wide MR revealed MTR as protective in chronic GN and HCK as a risk factor for membranous nephropathy, whereas CD302 and CDKN1B showed protective effects. Transcriptomic-wide MR identified candidate genes across GN subtypes: RECQL, BRSK2, and MGP in acute GN; AFM, CFHR5, and EPHB2 in chronic GN; IL6R, MBL2, and PRSS3 in IgA nephropathy; and TIMP4, HCK, and PEAR1 in membranous nephropathy. Bayesian colocalization analysis provided strong support for shared causal variants (PPH4 > 0.8) for HCK, CD302, TIMP4, PEAR1, PARP1, and FHIT. Replication and meta-analysis in the FinnGen cohort provided additional consistency across datasets, while downstream translational annotations highlighted IL6R, MBL2, C5, and CD55 as potential hub targets within immune and complement-related pathways. This integrative multi-omics study provides novel insights into the genetic architecture and therapeutic landscape of GN, identifying potential therapeutic targets that may inform precision nephrology and drug repurposing. Notably, most targets supported by colocalization, mouse knockout phenotypes, and drug repurposing evidence were predominantly identified in membranous nephropathy, suggesting a particularly tractable genetic and therapeutic architecture for this subtype.