Phenome-Wide Mendelian Randomization Analysis of the Plasma Proteins, Immune Cell Types, and Immune Cell Traits in IgAN

Background: IgA nephropathy (IgAN) remains the most frequent primary glomerular disease worldwide with poor outcomes leading to end-stage renal disease. Although there were significant advances in the understanding of the pathogenesis of IgAN in the past decade, an unmet need exists for further knowledge on the contribution and cause-effect of each cell type and protein in its pathogenesis. Methods: We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) to identify potential causal factors of IgAN (Kiryluk Lab, N=26734) among 791 plasm proteins, 17 circulating immune cells and 731 immune cell traits (118 absolute cell counts, 389 MFIs of surface antigens and 32 morphological parameters, 192 relative ratios between cell counts). FinnGen database (N=412181) of IgAN was applied for genetic replication. Reverse MR and Bayesian co-localization were performed to consolidate the results. Further, GO and KEGG pathway enrichment and protein-protein interaction of the putative proteins fowling hub module and hue genes were conducted to search for the underlying mechanism. Results: As for the MR-pheWAS of the pQTLs, CFH was identified as a significant protective factor for IgAN (OR 0.54, 95%CI [0.45,0.65], P=1.47E-10), while CFHR1 (OR 1.21, [1.12,1.31], P=8.49E-07) and ERAP2 (OR 1.14, [1.07,1.21], P=7.33E-06) showed as the risk factors. Additional 5 common putative proteins are suggestive in both datasets. As for the circulating immune cell types, it indicated a causal association between neutrophil (OR 1.64, [1.30,2.08], P=3.95E-05), white blood cell (OR 1.47, [1.20,1.81], P=2.32E-04) and an increased risk of IgAN. Activated & secreting Treg %CD4+, CD25hi %CD4+, T cell absolute count (AC), CD4+ AC, and Central memory (CM) CD4+ AC were indicated as the top 5 risk immune cell traits of IgAN. Enrichment analysis showed the complement activation cascade is a key pathway. Conclusion: Our results showed causal-effect clues of some key proteins, cell types, and cell traits in IgAN, highlighting complement and certain CD4+ T cells may warrant further mechanism investigation and therapy development.