title: TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits.
abstract: Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3 x 10(-21)), A928V (rs35018800, OR = 0.53, P = 1.2 x 10(-9)), and I684S (rs12720356, OR = 0.86, P = 4.6 x 10(-7)). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6 x 10(-18)), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; P(omnibus) = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America.
authors: Dorothée
authors: D
authors: Diogo
authors: Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Lisa
authors: L
authors: Bastarache
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Katherine P
authors: KP
authors: Liao
authors: ITGR Human Genetics Group, Genentech Inc, San Francisco, California, United States of America.
authors: Robert R
authors: RR
authors: Graham
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Robert S
authors: RS
authors: Fulton
authors: New York University Hospital for Joint Diseases, New York, New York, United States of America.
authors: Jeffrey D
authors: JD
authors: Greenberg
authors: Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors: Steve
authors: S
authors: Eyre
authors: Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors: John
authors: J
authors: Bowes
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Jing
authors: J
authors: Cui
authors: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, United States of America.
authors: Annette
authors: A
authors: Lee
authors: Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.
authors: Dimitrios A
authors: DA
authors: Pappas
authors: The Albany Medical College and The Center for Rheumatology, Albany, New York, United States of America.
authors: Joel M
authors: JM
authors: Kremer
authors: Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors: Anne
authors: A
authors: Barton
authors: Radboud university medical center, Radboud Institute for Health Sciences, Department of Human Genetics, Nijmegen, The Netherlands.
authors: Marieke J H
authors: MJ
authors: Coenen
authors: Radboud University Medical Center, Donders Centre for Neurosciences, Department of Psychiatry and Human Genetics, Nijmegen, The Netherlands.
authors: Barbara
authors: B
authors: Franke
authors: Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors: Lambertus A
authors: LA
authors: Kiemeney
authors: Université Paris-Sud, Orsay, France; APHP-Hôpital Bicêtre, INSERM U1012, Le Kremlin Bicêtre, Paris, France.
authors: Xavier
authors: X
authors: Mariette
authors: Université Paris-Sud, Orsay, France; APHP-Hôpital Bicêtre, INSERM U1012, Le Kremlin Bicêtre, Paris, France.
authors: Corrine
authors: C
authors: Richard-Miceli
authors: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Rheumatology Department, Santa Maria Hospital-CHLN, Lisbon, Portugal.
authors: Helena
authors: H
authors: Canhão
authors: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Rheumatology Department, Santa Maria Hospital-CHLN, Lisbon, Portugal.
authors: João E
authors: JE
authors: Fonseca
authors: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center /University of Amsterdam, Amsterdam, The Netherlands.
authors: Niek
authors: N
authors: de Vries
authors: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center /University of Amsterdam, Amsterdam, The Netherlands.
authors: Paul P
authors: PP
authors: Tak
authors: Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands.
authors: J Bart A
authors: JB
authors: Crusius
authors: Amsterdam Rheumatology and Immunology Center, Department of Rheumatology, Reade, Amsterdam, The Netherlands.
authors: Michael T
authors: MT
authors: Nurmohamed
authors: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Fina
authors: F
authors: Kurreeman
authors: Division of Rheumatology and Immunology, Omaha VA and University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors: Ted R
authors: TR
authors: Mikuls
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Yukinori
authors: Y
authors: Okada
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Eli A
authors: EA
authors: Stahl
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: David E
authors: DE
authors: Larson
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Tracie L
authors: TL
authors: Deluca
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Michelle
authors: M
authors: O'Laughlin
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Catrina C
authors: CC
authors: Fronick
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Lucinda L
authors: LL
authors: Fulton
authors: Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America.
authors: Roman
authors: R
authors: Kosoy
authors: Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America.
authors: Michael
authors: M
authors: Ransom
authors: ITGR Human Genetics Group, Genentech Inc, San Francisco, California, United States of America.
authors: Tushar R
authors: TR
authors: Bhangale
authors: ITGR Human Genetics Group, Genentech Inc, San Francisco, California, United States of America.
authors: Ward
authors: W
authors: Ortmann
authors: Information Systems, Partners Healthcare, Charlestown, Massachusetts, United States of America.
authors: Andrew
authors: A
authors: Cagan
authors: Information Systems, Partners Healthcare, Charlestown, Massachusetts, United States of America.
authors: Vivian
authors: V
authors: Gainer
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Elizabeth W
authors: EW
authors: Karlson
authors: Information Systems, Partners Healthcare, Charlestown, Massachusetts, United States of America.
authors: Isaac
authors: I
authors: Kohane
authors: Information Systems, Partners Healthcare, Charlestown, Massachusetts, United States of America.
authors: Shawn N
authors: SN
authors: Murphy
authors: Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, 18100, Spain.
authors: Javier
authors: J
authors: Martin
authors: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands; Genetics Department, University Medical Center and Groningen University, Groningen, The Netherlands.
authors: Alexandra
authors: A
authors: Zhernakova
authors: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Lars
authors: L
authors: Klareskog
authors: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Leonid
authors: L
authors: Padyukov
authors: Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors: Jane
authors: J
authors: Worthington
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Elaine R
authors: ER
authors: Mardis
authors: Division of Rheumatology and Immunology, Omaha VA and University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors: Michael F
authors: MF
authors: Seldin
authors: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, United States of America.
authors: Peter K
authors: PK
authors: Gregersen
authors: ITGR Human Genetics Group, Genentech Inc, San Francisco, California, United States of America.
authors: Timothy
authors: T
authors: Behrens
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America; Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors: Soumya
authors: S
authors: Raychaudhuri
authors: Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Joshua C
authors: JC
authors: Denny
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Robert M
authors: RM
authors: Plenge
mesh_terms: D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics*; D015551:Autoimmunity / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics; D057286:Electronic Health Records; D005091:Exons / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D053634:TYK2 Kinase / Q000235:genetics*
chemical_list: D015815:Cell Adhesion Molecules; D053634:TYK2 Kinase