Exploration of the genetic architecture of ANCA-associated vasculitis.

@article{byun2026exploration,
  title = {{Exploration of the genetic architecture of ANCA-associated vasculitis.}},
  author = {Jinyoung Byun and Vikram R. Shaw and Catherine Zhu and Younghun Han and Ryan Sun and Zhihui Zhang and Xiangjun Xiao and Benjamin D. Pinder and Jinyi Zhang and Yohannes Tadesse and Thomas R. Riley and Sharon Chung and David Cuthbertson and Paul F. Dellaripa and Anisha B. Dua and Ora Gewurz-Singer and Lindsy J. Forbess and Carol A. Langford and Nader Khalidi and Curry Koening and Alfred D. Mahr and Carol McAlear and Paul A. Monach and Larry Moreland and Christian Pagnoux and E. Philip Seo and Ulrich Specks and Robert F. Spiera and Antoine Sreih and Jason M. Springer and E. William St. Clair and Kenneth J. Warrington and Steven R. Ytterberg and Jeffrey C. Edberg and Peter C. Grayson and David Jayne and Rona Smith and Michael Walsh and Peter A. Merkel and Katherine A. Siminovitch and Christopher I. Amos and Simon Carette and Sharon Chung and Anisha Dua and Lindsy Forbess and Ora Gewurz-Singer and Nader Khalidi and Curry Koening and Carol A. Langford and Carol A. McAlear and Peter A. Merkel and Paul A. Monach and Larry Moreland and Christian Pagnoux and E. Philip Seo and Ulrich Specks and Robert F. Spiera and Jason Springer and Kenneth Warrington},
  journal = {EBioMedicine},
  year = {2026},
  month = oct,
  doi = {10.1016/j.ebiom.2026.106502},
  url = {https://europepmc.org/article/MED/42874292},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - Exploration of the genetic architecture of ANCA-associated vasculitis.
AU  - Jinyoung Byun
AU  - Vikram R. Shaw
AU  - Catherine Zhu
AU  - Younghun Han
AU  - Ryan Sun
AU  - Zhihui Zhang
AU  - Xiangjun Xiao
AU  - Benjamin D. Pinder
AU  - Jinyi Zhang
AU  - Yohannes Tadesse
AU  - Thomas R. Riley
AU  - Sharon Chung
AU  - David Cuthbertson
AU  - Paul F. Dellaripa
AU  - Anisha B. Dua
AU  - Ora Gewurz-Singer
AU  - Lindsy J. Forbess
AU  - Carol A. Langford
AU  - Nader Khalidi
AU  - Curry Koening
AU  - Alfred D. Mahr
AU  - Carol McAlear
AU  - Paul A. Monach
AU  - Larry Moreland
AU  - Christian Pagnoux
AU  - E. Philip Seo
AU  - Ulrich Specks
AU  - Robert F. Spiera
AU  - Antoine Sreih
AU  - Jason M. Springer
AU  - E. William St. Clair
AU  - Kenneth J. Warrington
AU  - Steven R. Ytterberg
AU  - Jeffrey C. Edberg
AU  - Peter C. Grayson
AU  - David Jayne
AU  - Rona Smith
AU  - Michael Walsh
AU  - Peter A. Merkel
AU  - Katherine A. Siminovitch
AU  - Christopher I. Amos
AU  - Simon Carette
AU  - Sharon Chung
AU  - Anisha Dua
AU  - Lindsy Forbess
AU  - Ora Gewurz-Singer
AU  - Nader Khalidi
AU  - Curry Koening
AU  - Carol A. Langford
AU  - Carol A. McAlear
AU  - Peter A. Merkel
AU  - Paul A. Monach
AU  - Larry Moreland
AU  - Christian Pagnoux
AU  - E. Philip Seo
AU  - Ulrich Specks
AU  - Robert F. Spiera
AU  - Jason Springer
AU  - Kenneth Warrington
PY  - 2026
DA  - 2026/10/14
JO  - EBioMedicine
DO  - 10.1016/j.ebiom.2026.106502
UR  - https://europepmc.org/article/MED/42874292
AB  - 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 (h² = 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.
SN  - 2352-3964
ER  -