IgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at the HLA-DRB1 (OR=1.55, P=1.1×10-25) and fine-mapped specific amino-acid risk substitutions in DRβ1. We discovered two novel non-HLA loci: FCAR (OR=1.51, P=1.0×10-20) encoding a myeloid IgA receptor FcαR, and INPP5D (OR=1.34, P=2.2×10-9) encoding a known inhibitor of FcαR signaling. The FCAR risk locus co-localized with a cis-eQTL increasing FCAR expression; the risk alleles disrupted a PRDM1 binding motif within a myeloid enhancer of FCAR. Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated by FCAR, INPP5D and IL6R in myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel loci PAID4, WLS, and ANKRD55.

2nd Department of Nephrology Hypertension and Internal Medicine Medical University of Bialystok Poland

Center for Research on Inflammation Paris Cité University INSERM and CNRS Paris France

Chan Zuckerberg Biohub New York New York NY USA

Children's Foundation Research Institute Le Bonheur Children's Hospital Memphis Tennessee

CIBSS Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg Germany

Cinncinnati Children's Hospital Cincinnati OH USA

Cleveland Clinic Cleveland OH USA

Columbia University Medical Center New York NY US

Connecticut Children's Medical Center Hartford CT USA

Danderyd University Hospital Karolinska Institute Stockholm Sweden

Department of Biochemistry and Molecular Biophysics Vagelos College of Physicians and Surgeons Columbia University New York NY USA

Department of Biomedical Informatics Vagelos College of Physicians and Surgeons Columbia University New York NY USA

Department of Clinical Immunology Medical University of Warsaw Warsaw Poland

Department of Dermatology and Pediatric Dermatology Centre of Postgraduate Medical Education Warsaw Poland

Department of Dermatology Medical University of Warsaw Warsaw Poland

Department of Genetics Medical University of Poznan Poznan Poland

Department of Medical and Surgical Specialties and Nephrology Unit University of Brescia ASST Spedali Civili Brescia Italy

Department of Medicine Division of Nephrology Columbia University College of Physicians and Surgeons New York NY USA

Department of Medicine Vagelos College of Physicians and Surgeons Columbia University New York NY USA

Department of Nephrology 1st School of Medicine Charles University Prague Czech Republic

Department of Nephrology and Hypertension Inselspital Bern University Hospital University of Bern Bern Switzerland

Department of Nephrology Transplantology and Internal Diseases Poznan University of Medical Sciences Poznan Poland

Department of Nephrology Transplantology and Internal Diseases University of Warmia and Mazury Olsztyn Poland

Department of Non Procedural Clinical Sciences Faculty of Medicine Wroclaw University of Science and Technology Wroclaw Poland

Department of Paediatrics Immunology and Nephrology Polish Mother's Memorial Hospital Research Institute Lodz Poland

Department of Pediatric Nephrology and Hypertension Faculty of Medicine Jagiellonian University Medical College Krakow Poland

Department of Pediatric Nephrology and Hypertension Jagiellonian University Medical College Krakow Poland

Department of Pediatric Nephrology Medical University of Lublin Lublin Poland

Department of Pediatrics and Nephrology Medical University of Warsaw 02 091 Warsaw Poland

Department of Pediatrics Faculty of Medical Sciences in Zabrze Medical University of Silesia Katowice Poland

Department of Pediatrics University of Tennessee Health Sciences Center Memphis Tennessee

Department of Pediatrics University of Washington; and Division of Nephrology Seattle Children's Hospital

Department of Pediatrics University of Zielona Góra Zielona Góra Poland

Department of Systems Biology Columbia University New York NY USA

Department of Transplantology Immunology Nephrology and Internal Diseases Medical University of Warsaw Warsaw Poland

Division of Nephrology Saint Louis University Saint Louis MO USA

Division of Neuroimmunology Department of Neurology Columbia University New York NY USA

Division of Pediatric Nephrology Department of Medicine Columbia University New York NY USA

Division of Pediatric Nephrology University of Kentucky Kentucky Children's Hospital Lexington KY USA

Division of Rheumatology IIS Fundación Jiménez Díaz Madrid Spain

Driscoll Children's Hospital Corpus Christi TX USA

East Carolina University Greenville NC USA

Helen DeVos Children's Hospital Grand Rapids MI USA

Herbert Irving Comprehensive Cancer Center Columbia University New York NY USA

Institute of Clinical Medicine Vilnius University Vilnius Lithuania

Institute of Genetic Epidemiology Medical Center and Faculty of Medicine University of Freiburg Freiburg Germany

Institute of Parasitology and Biomedicine Lopez Neyra Spanish National Research Council Granada Spain

IRCCS Istituto Giannina Gaslini Genoa Italy

Istituti Clinico Scientifici Maugeri IRCCS University of Pavia Pavia Italy

Maria Fareri Children's Hospital New York Medical College New York NY USA

Medical College of Wisconsin Madison WI USA

Medicine and Psychiatry Department University of Cantabria Santander Spain

MONICA BODRIA MD PHD Primary Care Unit Ausl Parma south east district Parma Italy

Mott Children's Hospital University of Michigan Ann Arbor MI USA

Nantes University Inserm CR2TI Center of Research on Translational Transplantation and Immunology Nantes France

Nationwide Children's Hospital Columbus OH USA

Nephrology and Dialysis A R N A S Civico and Benfratellio Palermo Italy

Phoenix Children's Hospital Phoenix AZ USA

Renal Dialysis and Transplant Unit Department of Pharmacy Health and Nutritional Sciences University of Calabria

Renal Division Peking University 1st Hospital Peking University Institute of Nephrology Beijing China

SUNY Buffalo Buffalo NY USA

Texas Children's Hospital Baylor College of Medicine Houston TX USA

Texas Tech University Health Sciences Center Amarillo TX USA

University of Alabama at Birmingham Birmingham AL USA

University of California in Los Angeles CA USA

University of Minnesota Minneapolis MN USA

University of Tennessee Health Science Center Memphis TN USA

University of Turin Italy

University of Utah Salt Lake City UT USA

UT Health San Antonio San Antonio TX USA

Valley Children's Healthcare Madera CA USA

Washington University in Saint Louis MO USA

Weill Cornell Medical Center New York NY USA

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