Shared genetic architecture and potential comorbid mechanisms between rheumatoid arthritis and idiopathic pulmonary...

Rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF) commonly coexist, notably in RA-associated interstitial lung disease. Despite clinical overlap, their shared genetic underpinnings remain poorly understood.

Using large-scale genome-wide association study (GWAS) data from European populations, we assessed genetic correlations between RA and IPF through linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Pleiotropic SNPs and shared loci were identified via pleiotropic analysis under the composite null hypothesis (PLACO), functional mapping and annotation of genetic associations (FUMA), and Bayesian colocalization. Multi-marker Analysis of GenoMic Annotation (MAGMA) pinpointed pleiotropic genes, followed by functional enrichment, transcription factor, cell-type specificity, and immune cell colocalization analyses.

Significant positive genetic correlations were identified (LDSC: rg = 0.321, P = 0.002; HDL: rg = 0.67, P = 5.01 × 10^-5). PLACO identified 212 pleiotropic SNPs across 11 risk loci, including 3 shared loci. MAGMA analysis detected 32 pleiotropic genes enriched in immune-related pathways, particularly IL-2 signaling and FOXP3 regulation. DisGeNET linked these genes with autoimmune and pulmonary diseases. Cell-type analyses indicated enrichment in naive T cells, pulmonary CD4⁺ memory effector T cells, and intestinal Paneth-like cells. Immune colocalization analyses highlighted multiple shared risk loci enriched in immune signals, notably at region 12q24.12.

Our findings reveal significant genetic correlations and potential shared genetic mechanisms between RA and IPF, identifying pleiotropic genes and loci involved in immune pathways. This provides foundational genetic insights for exploring pathogenesis and targeted therapies in RA-IPF comorbidity. Key Points • The genetic relationship between rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF) remains poorly understood despite their frequent clinical coexistence. • We applied genome-wide methods, including LDSC, HDL, PLACO, and MAGMA, to explore shared genetic architecture and immune mechanisms. • Our findings highlight potential common immune-regulatory pathways underlying RA-IPF comorbidity, offering new insights into pathogenesis and therapy development.