title: Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens.
abstract: We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kiryluk
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Yifu
authors.identifier: 0000000270777689
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1] Division of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Montichiari Hospital, University of Brescia, Brescia, Italy. [2] Department of Medical and Surgical Specialties, Radiological Sciences, University of Brescia, Brescia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Scolari
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Sanna-Cherchi
authors.affiliation: 1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Verbitsky
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fasel
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Sneh
authors.initials: S
authors.lastname: Lata
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Sindhuri
authors.initials: S
authors.lastname: Prakash
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Shapiro
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Fischman
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Snyder
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Appel
authors.affiliation: 1] Division of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Montichiari Hospital, University of Brescia, Brescia, Italy. [2] Prenatal Diagnosis Unit, Department of Obstetrics and Gynecology, University of Brescia, Brescia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Izzi
authors.affiliation: Division of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Spedali Civili Hospital, University of Brescia, Brescia, Italy.
authors.forename: Battista Fabio
authors.initials: BF
authors.lastname: Viola
authors.affiliation: 1] Division of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Montichiari Hospital, University of Brescia, Brescia, Italy. [2] Department of Medical and Surgical Specialties, Radiological Sciences, University of Brescia, Brescia, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Dallera
authors.affiliation: Renal Division, DMCO (Dipartimento di Medicina, Chirurgia e Odontoiatria), San Paolo Hospital, School of Medicine, University of Milan, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Del Vecchio
authors.affiliation: Renal Division, DMCO (Dipartimento di Medicina, Chirurgia e Odontoiatria), San Paolo Hospital, School of Medicine, University of Milan, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barlassina
authors.affiliation: Renal Division, DMCO (Dipartimento di Medicina, Chirurgia e Odontoiatria), San Paolo Hospital, School of Medicine, University of Milan, Milan, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.affiliation: 1] Immunogenetics and Biology of Transplantation, Città della Salute e della Scienza, University Hospital of Turin, Turin, Italy. [2] Medical Genetics, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: Francesca Eleonora
authors.initials: FE
authors.lastname: Bertinetto
authors.affiliation: 1] Immunogenetics and Biology of Transplantation, Città della Salute e della Scienza, University Hospital of Turin, Turin, Italy. [2] Medical Genetics, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Amoroso
authors.affiliation: Nephrology and Dialysis Unit, Ospedali di Cirié e Chivasso, Cirié, Turin, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Savoldi
authors.affiliation: Nephrology and Dialysis Unit, Ospedali di Cirié e Chivasso, Cirié, Turin, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rocchietti
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Regina Margheritra Hospital, Turin, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Amore
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Regina Margheritra Hospital, Turin, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Peruzzi
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Regina Margheritra Hospital, Turin, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Coppo
authors.affiliation: Division of Nephrology and Renal Transplantation, Carreggi Hospital, Florence, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Salvadori
authors.affiliation: 1] Department of Medicine, University of Calgary, Calgary, Alberta, Canada. [2] Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Pietro
authors.initials: P
authors.lastname: Ravani
authors.affiliation: Division of Nephrology Dialysis and Transplantation, Azienda Ospedaliero Universitaria Policlinico di Modena, Università di Modena e Reggio Emilia, Modena, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Magistroni
authors.affiliation: Division of Nephrology, Dialysis and Transplantation, Giannina Gaslini Institute, Genova, Italy.
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
authors.affiliation: Division of Nephrology, Dialysis and Transplantation, Giannina Gaslini Institute, Genova, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.affiliation: Division of Nephrology, Dialysis and Transplantation, Giannina Gaslini Institute, Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Bodria
authors.affiliation: Division of Nephrology, Dialysis and Transplantation, Giannina Gaslini Institute, Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lugani
authors.affiliation: 1] Division of Nephrology, Azienda Ospedaliero Universitaria, Parma, Italy. [2] Chair of Nephrology, University of Parma, Parma, Italy.
authors.forename: Landino
authors.initials: L
authors.lastname: Allegri
authors.affiliation: 1] Division of Nephrology, Azienda Ospedaliero Universitaria, Parma, Italy. [2] Chair of Nephrology, University of Parma, Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Delsante
authors.affiliation: 1] Division of Nephrology, Azienda Ospedaliero Universitaria, Parma, Italy. [2] Chair of Nephrology, University of Parma, Parma, Italy.
authors.forename: Mariarosa
authors.initials: M
authors.lastname: Maiorana
authors.affiliation: 1] Division of Nephrology, Azienda Ospedaliero Universitaria, Parma, Italy. [2] Chair of Nephrology, University of Parma, Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Magnano
authors.affiliation: Division of Nephrology, Dialysis and Renal Transplantation, Riuniti Hospital, Ancona, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Frasca
authors.affiliation: Division of Nephrology and Dialysis, Gorizia Hospital, Gorizia, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Boer
authors.affiliation: Division of Nephrology, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Trieste, Trieste, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Boscutti
authors.affiliation: Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ponticelli
authors.affiliation: Division of Nephrology and Dialysis, Infermi Hospital, Rimini, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Mignani
authors.affiliation: Division of Nephrology, Cannizzaro Hospital, Catania, Italy.
authors.forename: Carmelita
authors.initials: C
authors.lastname: Marcantoni
authors.affiliation: Division of Nephrology, Cannizzaro Hospital, Catania, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Di Landro
authors.affiliation: Chair of Nephrology, Division of Nephology and Dialysis, University of Messina, Azienda Ospedaliero-Universitaria Policlinico, Messina, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Santoro
authors.affiliation: Department of Nephrology and Dialysis, G. Brotzu Hospital, Cagliari, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Pani
authors.affiliation: Nephrology and Dialysis, Hospital of Viterbo, Viterbo, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Polci
authors.affiliation: Nephrology and Dialysis, Hospital of Viterbo, Viterbo, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Feriozzi
authors.affiliation: Division of Nephrology and Dialysis, Sandro Pertini Hospital, Rome, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Chicca
authors.affiliation: Division of Nephrology and Dialysis, Sandro Pertini Hospital, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Galliani
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Gigante
authors.affiliation: Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
authors.affiliation: Department of Nephrology, Second University of Naples, Naples, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Zamboli
authors.affiliation: Unità Operativa di Nefrologia e Dialisi, Ospedale di Acireale, Acireale, Italy.
authors.forename: Giovanni Giorgio
authors.initials: GG
authors.lastname: Battaglia
authors.affiliation: Unità Operativa di Nefrologia e Dialisi, Ospedale di Acireale, Acireale, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Garozzo
authors.affiliation: Department of Nephrology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic.
authors.forename: Dita
authors.initials: D
authors.lastname: Maixnerová
authors.affiliation: Department of Nephrology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tesar
authors.affiliation: 1] Department of Nephrology, RWTH (Rheinisch-Westfälische Technische Hochschule) University of Aachen, Aachen, Germany. [2] Kidney Diseases Research, Bayer Pharma, Wuppertal, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
authors.affiliation: Department of Nephrology, RWTH (Rheinisch-Westfälische Technische Hochschule) University of Aachen, Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.affiliation: Department of Nephrology, RWTH (Rheinisch-Westfälische Technische Hochschule) University of Aachen, Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.affiliation: 1] Nephrology Center, Medical Faculty, University of Pécs, Pécs, Hungary. [2] Second Department of Internal Medicine, Medical Faculty, University of Pécs, Pécs, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kovacs
authors.affiliation: 1] Nephrology Center, Medical Faculty, University of Pécs, Pécs, Hungary. [2] Second Department of Internal Medicine, Medical Faculty, University of Pécs, Pécs, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Nagy
authors.affiliation: Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mucha
authors.affiliation: Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Leszek
authors.initials: L
authors.lastname: Pączek
authors.affiliation: Krysiewicza Children's Hospital, Poznań, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Zaniew
authors.affiliation: Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Mizerska-Wasiak
authors.affiliation: Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Roszkowska-Blaim
authors.affiliation: Department of Nephrology, Transplantology and Internal Medicine, Poznan Medical University, Poznan, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Pawlaczyk
authors.affiliation: University College London Centre for Nephrology, Royal Free Hospital Pond Street, London, UK.
authors.forename: Daniel
authors.identifier: 0000000291701579
authors.initials: D
authors.lastname: Gale
authors.affiliation: 1] John Walls Renal Unit, University Hospitals of Leicester, Leicester, UK. [2] Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barratt
authors.affiliation: Department of Nephrology, Dialysis and Renal Transplantation, University North Hospital, Saint Etienne, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Thibaudin
authors.affiliation: Department of Nephrology, Dialysis and Renal Transplantation, University North Hospital, Saint Etienne, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Berthoux
authors.affiliation: 1] Service de Néphrologie Transplantation Adultes, Hôpital Necker-Enfants Malades, Paris, France. [2] INSERM, Institut Necker-Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Canaud
authors.affiliation: Centre National de Génotypage, Commissariat à l'Energie Atomique (CEA), Institut de Génomique, Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.affiliation: 1] INSERM, Centre for Research in Epidemiology and Population Health, Villejuif, France. [2] University Paris-Sud, Villejuif, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Metzger
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Division of Clinical Nephrology and Rheumatology, Niigata University, Niigata, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Goto
authors.affiliation: Division of Clinical Nephrology and Rheumatology, Niigata University, Niigata, Japan.
authors.forename: Ichiei
authors.initials: I
authors.lastname: Narita
authors.affiliation: Division of Nephrology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Yasar
authors.initials: Y
authors.lastname: Caliskan
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Xie
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Hou
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1] Division of Pediatric Nephrology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA. [2] Children's Foundation Research Center, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wyatt
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Novak
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Julian
authors.affiliation: 1] John Walls Renal Unit, University Hospitals of Leicester, Leicester, UK. [2] Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors.forename: John
authors.initials: J
authors.lastname: Feehally
authors.affiliation: 1] INSERM, Centre for Research in Epidemiology and Population Health, Villejuif, France. [2] University Paris-Sud, Villejuif, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Stengel
authors.affiliation: Renal Division, DMCO (Dipartimento di Medicina, Chirurgia e Odontoiatria), San Paolo Hospital, School of Medicine, University of Milan, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: 1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
mesh_terms: D017668:Age of Onset; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D039481:CD11b Antigen / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D058685:Genetic Pleiotropy / Q000235:genetics; D055106:Genome-Wide Association Study; D005922:Glomerulonephritis, IGA / Q000235:genetics*; D006681:HLA-D Antigens / Q000235:genetics*; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D007109:Immunity / Q000235:genetics*; D007422:Intestines / Q000276:immunology / Q000469:parasitology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics*
chemical_list: D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D039481:CD11b Antigen; D006681:HLA-D Antigens; C509295:ITGAM protein, human; D051567:Proto-Oncogene Proteins c-vav; C496621:VAV3 protein, human