Exploration of the genetic architecture of ANCA-associated vasculitis
Year: 2026
Type: article
Study design: Observational Study
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.
Source: EBioMedicine
Authors: Jinyoung Byun, Vikram R. Shaw, Catherine Zhu, Younghun Han, Ryan Sun, Zhihui Zhang, Xiangjun Xiao, Benjamin D. Pinder, Jinyi Zhang, Yohannes Tadesse, Thomas R. Riley, Sharon Chung, David Cuthbertson, Paul F. Dellaripa, Anisha B. Dua, Ora Gewurz-Singer, Lindsy J. Forbess, Carol A. Langford, Nader Khalidi, Curry Koening, Alfred D. Mahr, Carol McAlear, Paul A. Monach, Larry Moreland, Christian Pagnoux, E. Philip Seo, Ulrich Specks, Robert F. Spiera, Antoine Sreih, Jason M. Springer, E. William St. Clair, Kenneth J. Warrington, Steven R. Ytterberg, Jeffrey C. Edberg, Peter C. Grayson, David Jayne, Rona Smith, Michael Walsh, Peter A. Merkel, Katherine A. Siminovitch, Christopher I. Amos, Simon Carette, Sharon Chung, Anisha Dua, Lindsy Forbess, Ora Gewurz-Singer, Nader Khalidi, Curry Koening, Carol A. Langford, Carol A. McAlear, Peter A. Merkel, Paul A. Monach, Larry Moreland, Christian Pagnoux, E. Philip Seo, Ulrich Specks, Robert F. Spiera, Jason Springer, Kenneth Warrington
Institutions: University of New Mexico, Baylor College of Medicine, The University of Texas MD Anderson Cancer Center, Lunenfeld-Tanenbaum Research Institute, University of Pennsylvania, University of California, San Francisco, University of South Florida, Brigham and Women's Hospital, Northwestern University, University of Michigan, Cedars-Sinai Medical Center, Cleveland Clinic, McMaster University, University of Utah, Hôpital Saint-Louis, Boston University, University of Pittsburgh, Mount Sinai Hospital, University of Toronto, Johns Hopkins University, Mayo Clinic, Hospital for Special Surgery, University of Kansas Medical Center, Duke Medical Center, University of Alabama at Birmingham, National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, University of Cambridge
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,780
Funder: National Institutes of Health
OpenAlex ID: W7221754557