IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic

2nd Department of Internal Medicine Nephrological and Diabetological Center University of Pécs Pécs Hungary

2nd Department of Nephrology and Hypertension with Dialysis Unit Medical University of Bialystok Bialystok Poland

Amsterdam University Medical Centre VU University Medical Center Amsterdam the Netherlands

Assistance Publique Hôpitaux de Paris Service of Neuro Myology University Hospital Pitie Salpetriere Paris France

Azienda Unità Sanitaria Locale Rimini Rimini Italy

Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK

Belcolle Hospital Viterbo Italy

Biomedical Science Seoul National University College of Medicine Seoul Republic of Korea

CBP American Hospital Dubai United Arab Emirates

Center for Population Genomic Health Icahn School of Medicine at Mount Sinai New York City NY USA

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

Centre for Research in Epidemiology and Population Health Paris Saclay University Versailles Saint Quentin University INSERM Clinical Epidemiology Team Villejuif France

Children's Foundation Research Center Le Bonheur Children's Hospital Memphis TN USA

Cincinnati Children's Hospital Medical Center Cincinnati OH USA

Clinical Department of Nephrology and Transplantation Medicine Wroclaw Medical University Wroclaw Poland

CRTI Nantes University Nantes France

Department of Biostatistics Mailman School of Public Health Columbia University New York City NY USA

Department of Clinical Immunology Medical University of Warsaw Warsaw Poland

Department of Family Medicine Seoul National University College of Medicine and Seoul National University Hospital Seoul Republic of Korea

Department of Genetics and Genomic Sciences Mount Sinai Health System New York City NY USA

Department of Genetics Medical University of Poznan Poznan Poland

Department of Genetics Yale School of Medicine New Haven CT USA

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

Department of Internal Disease Nephrology and Dialysotherapy Military Institute of Medicine Warsaw Poland

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

Department of Medical Sciences University of Turin Turin Italy

Department of Medicine and Surgery University of Parma Parma Italy

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

Department of Microbiology and Immunology Laboratory of Molecular Immunology KU Leuven Leuven Belgium

Department of Nephrology and Dialysis ASST Lariana Como Italy

Department of Nephrology and Dialysis G Brotzu Hospital Cagliari Italy

Department of Nephrology and Hypertension Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

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

Department of Nephrology and Medical Intensive Care Charité Universitätsmedizin Berlin Berlin Germany

Department of Nephrology Danderyd University Hospital and Department of Clinical Sciences Karolinska Institutet Stockholm Sweden

Department of Nephrology Hypertension and Internal Medicine University of Warmia and Mazury in Olsztyn Olsztyn Poland

Department of Nephrology Juntendo University Faculty of Medicine Tokyo Japan

Department of Nephrology Karol Marcinkowski Hospital Zielona Góra Poland

Department of Nephrology Kidney Transplantation and Hypertension Children's Memorial Health Institute Warsaw Poland

Department of Nephrology Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China

Department of Nephrology Transplantology and Internal Diseases Medical University of Gdansk Gdansk Poland

Department of Nephrology Transplantology and Internal Medicine Poznan Medical University Poznan Poland

Department of Nephrology University of Toronto Toronto General Hospital Toronto Ontario Canada

Department of Pathology Medical University of Warsaw Warsaw 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 Warsaw Poland

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

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

Department of Pediatrics University of Zielona Góra Zielona Góra Poland

Department of Renal Medicine University College London London UK

Department of Surgical Medical Dental Oncologic and Regenerative Medicine University of Modena and Reggio Emilia Modena Italy

Department of Transplantation Medicine Nephrology and Internal Diseases Medical University of Warsaw Warsaw Poland

Departments of Microbiology and Medicine University of Alabama at Birmingham Birmingham AL USA

Departments of Neurology and Genetics Yale University New Haven CT USA

Division of Clinical Nephrology and Rheumatology Kidney Research Center Niigata University Graduate School of Medical and Dental Sciences Niigata Japan

Division of Inherited and Acquired Kidney Diseases Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University Moscow Russia

Division of Nephrology and Clinical Immunology RWTH Aachen University Aachen Germany

Division of Nephrology and Dialysis Gorizia Hospital Gorizia Italy

Division of Nephrology and Renal Transplantation Carreggi Hospital Florence Italy

Division of Nephrology Department of Internal Medicine University of Calgary Calgary Alberta Canada

Division of Nephrology Dialysis and Renal Transplantation Riuniti Hospital Ancona Italy

Division of Nephrology Dialysis and Transplantation IRCCS Giannina Gaslini Institute Genova Italy

Division of Nephrology Saint Louis University Saint Louis MO USA

Division of Nephrology University Hospitals Leuven Leuven Belgium

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

Division of Pediatric Nephrology Boston Children's Hospital Boston MA USA

Division of Pediatric Nephrology Department of Pediatrics HMH Hackensack University Medical Center Hackensack NJ USA

Division of Pediatric Nephrology Department of Pediatrics Nationwide Children's Hospital Columbus OH USA

Division of Pediatric Nephrology Department of Pediatrics New York Medical College New York City NY USA

Division of Pediatric Nephrology Department of Pediatrics The Medical University of South Carolina Charleston SC USA

Division of Pediatric Nephrology Department of Pediatrics University of Kentucky Lexington KY USA

Division of Pediatric Nephrology Department of Pediatrics University of Utah Salt Lake City UT USA

Division of Pediatric Nephrology Department of Pediatrics Weill Cornell Medical College New York City NY USA

Division of Pediatric Nephrology Driscoll Children's Hospital Corpus Christi TX USA

Division of Pediatric Nephrology Helen DeVos Children's Hospital Grand Rapids MI USA

Division of Pediatric Nephrology Mattel Children's Hospital Los Angeles CA USA

Division of Pediatric Nephrology Medical College of Wisconsin Milwaukee WI USA

Division of Pediatric Nephrology Mott Children's Hospital Ann Arbor MI USA

Division of Pediatric Nephrology Nationwide Children's Hospital Columbus OH USA

Division of Pediatric Nephrology SUNY Buffalo Buffalo NY USA

Division of Pediatric Nephrology University of Kentucky Lexington KY USA

Division of Pediatric Nephrology University of Minnesota Minneapolis MN USA

Division of Pediatric Nephrology University of Tennessee Health Sciences Center Memphis TN USA

Hospital Universitario Puerta del Hierro Majadahonda REDINREN IISCIII Madrid Spain

ICS Maugeri SpA University of Pavia Pavia Italy

Institute for Genomic Medicine Columbia University New York City NY USA

Institute of Biochemistry and Biophysics Polish Academy of Sciences Warsaw Poland

Institute of Clinical Molecular Biology Christian Albrechts University of Kiel Kiel Germany

Institute of Genetic Epidemiology Department of Genetics and Pharmacology Medical University of Innsbruck Innsbruck Austria

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

Institute of Human Genetics Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Institute on Aging Seoul National University College of Medicine Seoul Republic of Korea

Internal Medicine Seoul National University College of Medicine Seoul Republic of Korea

John Walls Renal Unit University Hospitals of Leicester Leicester UK

Laboratory of Human Genetics and Genomics The Rockefeller University New York City NY USA

Molecular Biology Laboratory and Nephrology Department Fundació Puigvert Instituto de Investigaciones Biomédicas Sant Pau Universitat Autònoma de Barcelona REDINREN IISCIII Barcelona Spain

NephroCare Italy Naples Italy

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

Nephrology and Dialysis Ospedale Maggiore Milan Italy

Nephrology and Dialysis Unit G Bosco Hub Hospital and University of Torino Torino Italy

Nephrology Dialysis and Kidney Transplant Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Università degli Studi di Milano Milan Italy

Nephrology Dialysis and Renal Transplant Unit S Maria della Misericordia Hospital ASUFC Udine Italy

Nephrology Dialysis and Renal Transplantation Department University North Hospital Saint Etienne France

Nephrology Dialysis and Transplantation Unit Department of Emergency and Organ Transplantation University of Bari Aldo Moro Bari Italy

Nephrology Division San Marco Hospital Catania Italy

Nephrology Service Hospital Británico de Buenos Aires Buenos Aires Argentina

Novo Nordisk Foundation Center for Basic Metabolic Research Department of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Regina Margherita Children's Hospital Torino Italy

Renal Division Dipartimento di Medicina Chirurgia e Odontoiatria San Paolo Hospital School of Medicine University of Milan Milan Italy

Renal Division DMCO San Paolo Hospital School of Medicine University of Milan Milan Italy

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

Renal Unit Department of Medicine University of Verona Verona Italy

Robert S Boas Center for Genomics and Human Genetics Feinstein Institutes for Medical Research North Shore LIJ Health System New York City NY USA

S Andrea Hospital La Spezia Italy

Salford Royal Hospital Salford UK

San Raffaele Hospital Milan Italy

Sandro Pertini Hospital Rome Italy

Sorbonne University INSERM Center of Research in Myology Institute of Myology University Hospital Pitie Salpetriere Paris France

The Aristotle University of Thessaloniki Thessaloniki Greece

The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York City NY USA

Unit of Nephrology and Dialysis AOU G Martino University of Messina Messina Italy

Unit of Nephrology and Dialysis ASL TO4 Consultorio Cirié Turin Italy

Unità Operativa di Nefrologia e Dialisi Ospedale di Acireale Acireale Italy

Université de Paris Hôpital Necker Enfants Malades Paris France

University of Cincinnati College of Medicine Cincinnati OH USA

University of Groningen Groningen the Netherlands

University of Hamburg Hamburg Germany

University of Messina Messina Italy

US Department of Veterans Affairs Medical Center and Cincinnati Education and Research for Veterans Foundation Cincinnati OH USA

Zagreb Medical School Zagreb Croatia

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Am J Kidney Dis. 2024 Jan;83(1):108-111. doi: 10.1053/j.ajkd.2023.09.001. PubMed

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Genome-wide studies define new genetic mechanisms of IgA vasculitis

IgA nephropathy