Genome-wide studies define genetic mechanisms of IgA vasculitis

IgA vasculitis is a pediatric disease with skin and systemic manifestations. Here, we conduct genome, transcriptome, and proteome-wide association studies in 2170 IgA vasculitis cases and 5928 controls, generate IgA vasculitis-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstruct myeloid-specific regulatory networks to define disease master regulators modulated by the identified genes. We observe significant association at the HLA-DRB1 locus (OR = 1.55, P = 1.1 × 10−25) and fine-map specific amino-acid risk substitutions in DRβ1. We find two novel non-HLA associated loci: FCAR (OR = 1.51, P = 1.0 × 10−20), encoding a myeloid IgA receptor FcαR, and INPP5D (OR = 1.34, P = 2.2 × 10−09), encoding an inhibitor of FcαR signalling. The FCAR risk locus co-localizes with a cis-eQTL that increases FCAR expression; the risk alleles disrupt a PRDM1 binding motif within a myeloid enhancer of FCAR. Another risk locus is associated with higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carries a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Applying network-based approaches to blood single cell transcriptomes, we predict, independently replicate, and experimentally validate 21 IgA vasculitis master regulators co-modulated by FCAR, INPP5D and IL6R signalling in myeloid cells. IgA vasculitis is a pediatric disease with skin and systemic manifestations. Here, the authors use multiomic data to examine the genetic mechanisms of IgA vasculitis and find therapeutically relevant immune pathways and molecular drivers.

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Journal
Nature Communications
Published
2026-10-15
DOI
https://doi.org/10.1038/s41467-026-78026-6
Primary Topic
Vasculitis and related conditions
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article
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article

Genome-wide studies define genetic mechanisms of IgA vasculitis

Dana V. Rizk, Sherene Mason, Fangming Lin, Krzysztof Mucha et al.
Nature Communications
Vasculitis and related conditions
article

Genome-wide studies define genetic mechanisms of IgA vasculitis

Dana V. Rizk, Sherene Mason, Fangming Lin, Krzysztof Mucha, Aftab S. Chishti, Masashi Fujita, Francesca Zanoni, Shu‐Feng Zhou, Joseph T. Flynn, Dave Selewski, Lukas J. Vlahos, Aaron Timothy Griffin, Qiao Shang, Michelle N. Rheault, Dmitry V. Samsonov, Dorota Kamińska, Claudia Izzi, Miguel Ángel González-Gay, Maddalena Marasà, Andrzej Badeński, Atlas Khan, Andrew S. Bomback, Krzysztof Pawlaczyk, Michał Florczak, Laila‐Yasmin Mani, Tetyana L. Vasylyeva, Robert J. Wyatt, Bruce A. Julian, Renato C. Monteiro, Sigrid Gertrud Gisela Lundberg, William E. Smoyer, Katarzyna Siniewicz‐Luzeńczyk, Agnieszka Gradzińska, Bartosz Foroncewicz, Jan Novák, Norbert Kwella, Cecilia C. Berrouet, Raed N. Bou Matar, Marcin Zaniew, Antonio Amoroso, Maria Szczepańska, Monica Bodria, Helena Krakowczyk, Guillermo Hidalgo, Edyta Machura, Francesca Lugani, Monika Miklaszewska, Luigi Biancone, Andrea Califano, Oleh M. Akchurin, Samhar I. Al-Akash, Francesco Scolari, Raji Sreedharan, Philip L. De Jager, Krzysztof Kiryluk, Colin Reily, Leszek Pączek, Bruno Vogt, Todd J. Green, Mahmoud Kallash, Dorota Drożdż, Scott E. Wenderfer, Augustina Jankauskienė, John D. Mahan, Laureline Berthelot, Jun Y. Zhang, Gianluigi Zaza, Patricia L. Weng, Javier J. Martin, Évangéline Pillebout, Anna Köttgen, Franca M. Iorember, Daniel Ranch, Cynthia Silva, Nianzhou Xiao, Sara Monteiro-Martins, Stacy D. Hall, Margaret Colleen Hastings, Przemysław Sikora, Vladimı́r Tesař, Małgorzata Olszewska, Ciro Esposito, Donna J. Claes, Anna Materna‐Kiryluk, Ali G. Gharavi, Tomasz Hryszko, Vittoria Esposito, Yaşar Çalışkan, Raoul D. Nelson, Lili Liu, Alejandro Quiroga, Thomas K. Davis, Luisa Bono, Gerald B. Appel, Shihong Qiu, Li Zhu, Malgorzata Mizerska-Wasiak, Alexandria D. Taylor, Hong Zhang
article en

Abstract

IgA vasculitis is a pediatric disease with skin and systemic manifestations. Here, we conduct genome, transcriptome, and proteome-wide association studies in 2170 IgA vasculitis cases and 5928 controls, generate IgA vasculitis-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstruct myeloid-specific regulatory networks to define disease master regulators modulated by the identified genes. We observe significant association at the HLA-DRB1 locus (OR = 1.55, P = 1.1 × 10−25) and fine-map specific amino-acid risk substitutions in DRβ1. We find two novel non-HLA associated loci: FCAR (OR = 1.51, P = 1.0 × 10−20), encoding a myeloid IgA receptor FcαR, and INPP5D (OR = 1.34, P = 2.2 × 10−09), encoding an inhibitor of FcαR signalling. The FCAR risk locus co-localizes with a cis-eQTL that increases FCAR expression; the risk alleles disrupt a PRDM1 binding motif within a myeloid enhancer of FCAR. Another risk locus is associated with higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carries a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Applying network-based approaches to blood single cell transcriptomes, we predict, independently replicate, and experimentally validate 21 IgA vasculitis master regulators co-modulated by FCAR, INPP5D and IL6R signalling in myeloid cells. IgA vasculitis is a pediatric disease with skin and systemic manifestations. Here, the authors use multiomic data to examine the genetic mechanisms of IgA vasculitis and find therapeutically relevant immune pathways and molecular drivers.

Nature Communications
University of Bern (CH), Wrocław University of Science and Technology (PL), Poznan University of Medical Sciences (PL), Medical University of Lublin (PL), University of Parma (IT), Jagiellonian University (PL), Cincinnati Children's Hospital Medical Center (US), Centre National de la Recherche Scientifique (FR), Seattle Children's Hospital (US), University of Minnesota (US), Universidad de Cantabria (ES), Nationwide Children's Hospital (US), Cleveland Clinic (US), Consejo Superior de Investigaciones Científicas (ES), University of Kentucky (US), Medical University of Białystok (PL), Inserm (FR), University of Tennessee Health Science Center (US), University of Freiburg (DE), University of California, Los Angeles (US), The University of Texas at San Antonio Health Science Center (US), Medical University of Silesia (PL), Vilnius University (LT), Baylor College of Medicine (US), East Carolina University (US), Medical College of Wisconsin (US), Washington University in St. Louis (US), Université Paris Cité (FR), Charles University (CZ), University of Utah (US), Medical University of Warsaw (PL), University of Michigan (US), Columbia University Irving Medical Center (US), University Hospital of Bern (CH), University Medical Center Freiburg (DE), Istituto Giannina Gaslini (IT), Karolinska Institutet (SE), University of Alabama at Birmingham (US), Istituti Clinici Scientifici Maugeri (IT), Connecticut Children's Medical Center (US), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Maria Fareri Children's Hospital (US), Children's Hospital Central California (US), Driscoll Children's Hospital (US), Phoenix Children's Hospital (US), Institute of Biochemistry and Biophysics, Polish Academy of Sciences (PL), Centre de Recherche sur l'Inflammation (FR), Helen DeVos Children's Hospital (US), Peking University First Hospital (CN), Polish Mother’s Memorial Hospital Research Institute (PL), Texas Children's Hospital (US), C. S. Mott Children's Hospital (US), Instituto de Parasitología y Biomedicina "López - Neyra" (ES), Le Bonheur Children's Hospital (US), Center for Research in Transplantation and Translational Immunology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (ES), Weill Cornell Medical Center (US), Abigail Wexner Research Institute (US), University of Calabria (IT), University of Zielona Góra (PL), Saint Louis University (US), University of Warmia and Mazury in Olsztyn (PL), University at Buffalo, State University of New York (US), Columbia University (US), University of Brescia (IT), Texas Tech University Health Sciences Center (US), Nantes Université (FR), Polish Academy of Sciences (PL)
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Vasculitis and related conditions
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