Single‐Cell Genetic Mapping of Gasdermin Expression Across Immune‐Mediated Inflammatory Diseases

The gasdermin (GSDM) family mediates pyroptosis and membrane pore formation, but the causal, cell-type-specific roles of individual paralogues in immune-mediated inflammatory diseases (IMIDs) remain poorly defined. We combined single-cell cis-eQTL data from 14 peripheral blood immune subsets (OneK1K) with genome-wide association data from FinnGen release 12 to perform lineage-resolved Mendelian randomization (MR) across eight IMIDs: ankylosing spondylitis, Behçet disease, Crohn disease, hidradenitis suppurativa, primary sclerosing cholangitis, psoriasis, rheumatoid arthritis, and ulcerative colitis (UC). We identified robust genetic instruments for GSDMA, GSDMB, and GSDMD. Higher GSDMA expression in naïve/central-memory CD4⁺ T cells was protective in UC and Crohn disease, whereas up-regulation in cytotoxic CD8⁺/natural-killer cells increased the risk for hidradenitis suppurativa and ankylosing spondylitis. GSDMB showed predominantly protective effects: increased expression in multiple T-cell subsets associated with lower risk of UC, Crohn disease, rheumatoid arthritis, and ankylosing spondylitis, but showed an opposite liability in primary sclerosing cholangitis. By contrast, higher GSDMD expression conferred risk in psoriasis and a weaker liability in ankylosing spondylitis, yet was protective in primary sclerosing cholangitis; no instruments were found for GSDMC or GSDME. Consistent with these genetic associations, an independent endoscopic-biopsy cohort (25 UC vs. 25 healthy controls) showed increased mucosal GSDMB protein, suggesting a context-dependent, potentially protective epithelial upregulation. Together, these results establish paralogue- and lineage-specific roles for gasdermins in IMIDs and highlight therapeutic opportunities for cell-targeted modulation of GSDM function.