Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci strati fi ed by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare in fl ammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) speci fi c for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identi fi es 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Strati fi cation by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO + ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO + ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.