Exploration of the genetic architecture of ANCA-associated vasculitis
Abstract
Background Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a complex autoimmune disease with distinct clinical and serological subtypes. Previous genome-wide association studies (GWAS) have identified several susceptibility loci, particularly within the major histocompatibility complex (MHC), but the broader genetic architecture and causal variants underlying AAV remain incompletely defined. Methods We conducted a genome-wide association study including 2068 individuals with AAV and 3258 controls of European ancestry. The discovery cohort comprised a previously published GWAS dataset supplemented with newly recruited cases. Analyses were stratified by clinical (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) and serological (proteinase 3–ANCA [PR3] and myeloperoxidase–ANCA [MPO]) subtypes. Findings were evaluated in an independent case cohort of 465 individuals. We performed conditional and joint analyses of the HLA region, functional fine-mapping, linkage disequilibrium score regression, and integrative multi-omics analyses to prioritise candidate causal variants and assess genetic correlations. Findings We identified eight previously unreported loci and replicated four known loci associated with AAV at genome-wide significance. Within the HLA region, HLA-DPB1∗04 showed the strongest association with AAV, GPA, and PR3 subtypes, whereas HLA-DRB1∗04 was most strongly associated with MPO and MPA. Conditional analyses identified additional independent effects, including amino acid variation in HLA-DQA1 . SNP-based heritability estimates indicated a substantial genetic contribution to AAV (h 2 = 0·40). Genetic correlation analyses revealed shared heritability with multiple traits, including celiac disease and hypothyroidism. Integrative analyses highlighted candidate genes, including HCG9 and PRTN3 , and implicated protein interaction networks involving genes related to neutrophil biology. Protein–protein interaction analysis identified networks involving genes implicated in AAV risk, including PRTN3 , AZU1 , ELANE , and SERPINA1 . Interpretation These findings expand the genetic landscape of AAV and support a complex and heterogeneous genetic architecture involving both MHC and non-MHC loci. The integration of genetic association, functional annotation, and network analyses suggests that disease susceptibility is mediated through multiple biological pathways, including immune regulation and neutrophil function. These insights may inform future mechanistic studies, improved disease stratification, and the development of targeted therapeutic strategies. Funding National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of General Medical Sciences.
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Authors: Jinyoung Byun, Vikram R. Shaw, Catherine Zhu, Younghun Han, Ryan Sun, Zhihui Zhang, Xiangjun Xiao, Benjamin D. Pinder, Jinyi Zhang, Yohannes Tadesse, Thomas Riley, David D Cuthbertson, Paul F. Dellaripa, Alfred Mahr, Antoine G. Sreih, E. William St. Clair, Kenneth J. Warrington, Steven R. Ytterberg, Jeffrey C. Edberg, Peter C. Grayson, David R.W. Jayne, Rona Smith, Michael Walsh, Katherine A. Siminovitch, Christopher Ian Amos, Simon Carette, Sharon A. Chung, Anisha B. Dua, Lindsy J. Forbess, Ora Gewurz‐Singer, NADER A. KHALIDI, Curry L. Koening, Carol A. Langford, Carol A. McAlear, Peter A. Merkel, Paul A. Monach, Larry Moreland, Christian Pagnoux, E. Philip Seo, Ulrich Specks, Robert Spiera, Jason Michael Springer, Kenneth H. Warrington
Institutions: Brigham and Women's Hospital, University of Pittsburgh, University of Pennsylvania, Northwestern University, Johns Hopkins University, University of Alabama at Birmingham, Hospital for Special Surgery, University of South Florida, University of California, San Francisco, University of Michigan, University of Toronto, Boston University, Cedars-Sinai Medical Center, The University of Texas MD Anderson Cancer Center, University of Utah, University of Cambridge, McMaster University, Duke Medical Center, Mayo Clinic, University of Kansas Medical Center, Baylor College of Medicine, National Institutes of Health, Cleveland Clinic, Lunenfeld-Tanenbaum Research Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Hôpital Saint-Louis, Mount Sinai Hospital, University of New Mexico Health Sciences Center