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

Area of Science:

• Genetics and Genomics
• Nephrology
• Immunology

Background:

• Glomerulonephritis (GN) is a major cause of kidney failure, driven by immune system dysfunction.
• Current treatments for GN have limited efficacy and significant side effects, necessitating new therapeutic strategies.
• Understanding the genetic underpinnings of GN is crucial for developing personalized medicine approaches.

Purpose of the Study:

• To systematically identify genetic risk and protective factors across four subtypes of glomerulonephritis (GN) using a multi-omics approach.
• To evaluate the translational potential of identified genetic targets for drug repurposing and precision nephrology.
• To investigate the genetic architecture of GN subtypes, with a focus on membranous nephropathy.

Main Methods:

• A systematic multi-omics Mendelian randomization (MR) analysis integrating proteomic and transcriptomic data with genome-wide association studies (GWAS) for four GN subtypes.
• Bayesian colocalization to confirm causal relationships between genetic variants and GN.
• Independent replication and meta-analysis using the FinnGen cohort, alongside mouse knockout phenotypes and drug repositioning analysis.

Main Results:

• Proteomic MR identified MTR (protective in chronic GN) and HCK (risk factor in membranous GN), with CD302 and CDKN1B also showing protective effects.
• Transcriptomic MR revealed candidate genes including RECQL, BRSK2, MGP (acute GN); AFM, CFHR5, EPHB2 (chronic GN); IL6R, MBL2, PRSS3 (IgA nephropathy); and TIMP4, HCK, PEAR1 (membranous GN).
• Bayesian colocalization supported causal variants for HCK, CD302, TIMP4, PEAR1, PARP1, and FHIT. IL6R, MBL2, C5, and CD55 emerged as key targets in immune and complement pathways, particularly for membranous nephropathy.

Conclusions:

• This integrative multi-omics study elucidates the genetic architecture of GN, identifying novel therapeutic targets.
• Findings support IL6R, MBL2, C5, and CD55 as potential therapeutic targets for precision nephrology and drug repurposing.
• Membranous nephropathy exhibits a particularly promising genetic and therapeutic landscape, with several targets showing strong translational potential.