Mechanism-centered target discovery across glomerulonephritis phenotypes: an integrative multi-omics study.

Area of Science:

• Genomics and Proteomics
• Immunology
• Nephrology

Background:

• Glomerulonephritis (GN) encompasses diverse immune-mediated kidney diseases.
• Current treatments often involve broad immunosuppression, highlighting the need for targeted therapies.
• Mechanism-informed drug discovery is crucial for various GN phenotypes.

Purpose of the Study:

• To integrate multi-omics data for identifying novel therapeutic targets in glomerulonephritis.
• To explore shared and phenotype-specific biological programs across the GN spectrum.
• To prioritize candidate genes for future drug development in kidney diseases.

Main Methods:

• Integrative multi-omics analysis combining cis-eQTL, cis-pQTL, and GWAS data.
• Candidate gene organization into four mechanistic programs: cytokine/TNF signaling, cell-cycle/senescence-repair, complement/innate immunity, and regulated cell-death/redox stress.
• Application of Bayesian colocalization, meta-analysis, and network pharmacology for target prioritization.

Main Results:

• Identified 42 transcriptomic and 12 proteomic putative targets, with enrichment in non-proliferative and primary membranoproliferative GN.
• Bayesian colocalization supported PPP2R1B, SOD1, and CDK4 for specific GN types.
• Complement/innate immunity and cytokine/TNF signaling emerged as dominant shared pathways; 31 non-MHC targets prioritized, including PPP2R1B, CDK4, and SOD1.

Conclusions:

• This study provides a mechanism-centered view of biological programs in glomerulonephritis.
• It identifies and prioritizes candidate targets for therapeutic development.
• The findings support a shift towards precision medicine in treating diverse GN phenotypes.