Shared genetic architecture between Crohn's disease and IgA nephropathy: implications for a gut-immune-kidney axis

Inflammatory bowel disease (IBD) and IgA nephropathy (IgAN) share features of mucosal immune dysregulation, but the genetic basis of their relationship and the contribution of specific IBD subtypes remain unclear.

Using public genome-wide association study (GWAS) summary datasets, we performed bidirectional Mendelian randomization (MR) analyses in European and East Asian populations, together with generalized summary-data-based Mendelian randomization (GSMR), Causal Analysis Using Summary Effect Estimates (CAUSE), genetic correlation, enrichment, cross-trait locus analysis, colocalization, and single-cell RNA sequencing. Phenotypic support was assessed in a clinical cohort of 9,371 patients with IBD.

Crohn's disease (CD), but not ulcerative colitis (UC), showed a consistent directional genetic association with IgAN across populations, and GSMR provided complementary support for this association (P = 4.02 × 10^-5). CAUSE did not clearly favor the causal model over the sharing model. Standard linkage disequilibrium score regression (LDSC) identified a positive genetic correlation between CD and IgAN (rg = 0.392, SE = 0.093, P = 2.53 × 10^-5), with constrained-intercept LDSC and genetic covariance analyzer (GNOVA) providing supportive evidence. Functional analyses showed enrichment in whole blood and spleen, but not kidney tissue. Integrative analyses prioritized ERAP2 and CARD9 as leading candidate genes, with the strongest colocalization support observed for ERAP2 in sigmoid-colon expression quantitative trait locus (eQTL) data (posterior probability of colocalization [PPH4] = 90.4%) and for CARD9 at the GWAS level (PPH4 = 98.4%). In the clinical cohort, biopsy-confirmed IgAN was more common in CD than in UC (Firth-adjusted OR = 3.40, 95% CI 1.28-11.28; P = 0.0125).

These findings support shared genetic architecture between CD and IgAN and suggest a possible directional genetic association between CD liability and IgAN risk. ERAP2 and CARD9 were prioritized as candidate genes within a proposed gut-immune-kidney framework.