Multi-omics triangulation identifies complement factor H as a genetically supported protective factor in IgA nephropathy

Background: IgA nephropathy is the most prevalent primary glomerulonephritis globally. Dysregulation of the complement system, specifically the alternative pathway, is a critical driver of its pathogenesis. While genome-wide association studies consistently map a primary susceptibility locus to the complement factor H gene cluster, extensive linkage disequilibrium and complex structural variations have historically obscured precise causal targets. Methods: We employed a multi-omics triangulation framework to evaluate the genetic association and potential protective effects of circulating complement proteins in IgA nephropathy. The analytical pipeline integrated large-scale plasma proteomics, blood-derived expression quantitative trait loci, Bayesian colocalization, computational clinical transcriptomics, and phenome-wide association studies. Two-sample, bidirectional, and multivariable Mendelian randomization analyses were performed using summary-level data from global genome-wide association studies. Results: Genetically predicted higher circulating levels of complement factor H were significantly associated with a lower risk of IgA nephropathy. Bayesian colocalization decoupled the complex locus, isolating this protective signal to a single missense variant within the complement factor H gene and demonstrating independence from the adjacent complement factor H-related 1 gene. Spatial profiling and clinical transcriptomics suggested a dual-compartment model: the liver supplies the systemic pool, while intrinsic renal cells mount a hypothesized severity-driven compensatory upregulation of complement factor H during active disease. Furthermore, phenome-wide association studies indicated that enhancing complement factor H offers dual protective benefits against IgA nephropathy and age-related macular degeneration without broad chronic systemic pleiotropy. Conclusions: This study provides convergent genomic and transcriptomic evidence supporting complement factor H as a genetically supported protective factor in IgA nephropathy. Genetic variation consistent with enhanced complement factor H-mediated regulation is associated with reduced disease susceptibility. These findings provide a theoretical framework for exploring direct recombinant supplementation therapies and offer genetic support for the ongoing clinical development of upstream alternative pathway inhibitors.