ArticlePloS one2015
TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits.
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Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers, 5 of them syntheses that pooled it.
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92citing papers in PubMed, 5 pooled it
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Who cites it
92 citing papers in PubMed, 5 syntheses or guidelines pooled it, 147 citations in OpenAlex.
- Association of germline TYK2 variation with lung cancer and non-Hodgkin lymphoma risk.International journal of cancer · 2022Pooled it
- Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.Nature genetics · 2022Pooled it
- Association of a rare variant of the TNFSF13B gene with susceptibility to Rheumatoid Arthritis and Systemic Lupus Erythematosus.Scientific reports · 2018Pooled it
- Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.Human molecular genetics · 2017Pooled it
- Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.Annals of the rheumatic diseases · 2016Pooled it
- Trial
- Population-Stratified Human Genetic Studies Are Not Eugenics: A Response to Donohue and Myles.Bioethics · 2026Article
- Deep mutational scanning reveals pharmacologically relevant insights into TYK2 signaling and disease.eLife · 2026Article
- Exome sequencing directly implicates 68 genes in inflammatory bowel disease.medRxiv : the preprint server for health sciences · 2026Article
- Pharmacological Characterization of GLPG3667, a Tyrosine Kinase 2-Selective Inhibitor, for the Treatment of Inflammatory and Autoimmune Diseases.Inflammation · 2026Article
- How Genomic and Structural Context Could Shape JAK-STAT Variant Pathogenicity.Twin research and human genetics : the official journal of the International Society for Twin Studies · 2026Article
- Genome-scale mapping of variant, enhancer and gene function in primary human CD4+ T cells.bioRxiv : the preprint server for biology · 2026Article
- Monogenic disorders of immunity: Common variants are not so rare.Cell genomics · 2026Review
- A genetics-guided integrative framework for drug repurposing: identifying antihypertensive drugs for type 2 diabetes.NPJ drug discovery · 2026Article
- Rare germline JAK/STAT variants in a Korean cohort amplify innate immune responses to vaccination.iScience · 2025Article
- Tyrosine kinase 2 inhibitors in the therapy of inflammatory and autoimmune diseases.Pharmacological reports : PR · 2025Review
- Investigation of the transcriptional impact of rare germline JAK/STAT variants found in a Tyrolean alpine community.BMC genomics · 2025Article
- Pathway Analysis Interpretation in the Multi-Omic Era.Biotech (Basel (Switzerland)) · 2025Review
- Early human migration determines the risk of being attacked by wolves: ethnic gene diversity on the development of systemic lupus erythematosus.Journal of rheumatic diseases · 2024Review
- Genetic variants regulating the immune response improve the prediction of COVID-19 severity provided by clinical variables.Scientific reports · 2024Article
32 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
54 authors at 20 institutions in 7 countries.
Dorothée DiogoDivision 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.
Lisa BastaracheDepartment of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States of America.
Katherine P LiaoDivision of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Robert R GrahamITGR Human Genetics Group, Genentech Inc, San Francisco, California, United States of America.
Robert S FultonThe Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Jeffrey D GreenbergNew York University Hospital for Joint Diseases, New York, New York, United States of America.
Steve EyreArthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
John BowesArthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Jing CuiDivision of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Annette LeeThe Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, United States of America.
Dimitrios A PappasColumbia University, College of Physicians and Surgeons, New York, New York, United States of America.
Joel M KremerThe Albany Medical College and The Center for Rheumatology, Albany, New York, United States of America.
Anne BartonArthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Marieke J H CoenenRadboud university medical center, Radboud Institute for Health Sciences, Department of Human Genetics, Nijmegen, The Netherlands.
Barbara FrankeRadboud University Medical Center, Donders Centre for Neurosciences, Department of Psychiatry and Human Genetics, Nijmegen, The Netherlands.
Lambertus A KiemeneyRadboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
Xavier MarietteUniversité Paris-Sud, Orsay, France; APHP-Hôpital Bicêtre, INSERM U1012, Le Kremlin Bicêtre, Paris, France.
Corrine Richard-MiceliUniversité Paris-Sud, Orsay, France; APHP-Hôpital Bicêtre, INSERM U1012, Le Kremlin Bicêtre, Paris, France.
Helena CanhãoRheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Rheumatology Department, Santa Maria Hospital-CHLN, Lisbon, Portugal.
João E FonsecaRheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Rheumatology Department, Santa Maria Hospital-CHLN, Lisbon, Portugal.
Niek de VriesAmsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center /University of Amsterdam, Amsterdam, The Netherlands.
Paul P TakAmsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center /University of Amsterdam, Amsterdam, The Netherlands.
J Bart A CrusiusLaboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands.
Michael T NurmohamedAmsterdam Rheumatology and Immunology Center, Department of Rheumatology, Reade, Amsterdam, The Netherlands.
Fina KurreemanDepartment of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
Ted R MikulsDivision of Rheumatology and Immunology, Omaha VA and University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Yukinori OkadaDivision 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.
Eli A StahlDivision 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.
David E LarsonThe Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Tracie L DelucaThe Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Michelle O'LaughlinThe Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Catrina C FronickThe Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Lucinda L FultonThe Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Roman KosoyDepartment of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America.
Michael RansomDepartment of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America.
Tushar R BhangaleITGR Human Genetics Group, Genentech Inc, San Francisco, California, United States of America.
Ward OrtmannITGR Human Genetics Group, Genentech Inc, San Francisco, California, United States of America.
Andrew CaganInformation Systems, Partners Healthcare, Charlestown, Massachusetts, United States of America.
Vivian GainerInformation Systems, Partners Healthcare, Charlestown, Massachusetts, United States of America.
Elizabeth W KarlsonDivision of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Isaac KohaneInformation Systems, Partners Healthcare, Charlestown, Massachusetts, United States of America.
Shawn N MurphyInformation Systems, Partners Healthcare, Charlestown, Massachusetts, United States of America.
Javier MartinInstituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, 18100, Spain.
Alexandra ZhernakovaDepartment of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands; Genetics Department, University Medical Center and Groningen University, Groningen, The Netherlands.
Lars KlareskogRheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
Leonid PadyukovRheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
Jane WorthingtonArthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Elaine R MardisThe Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Michael F SeldinDivision of Rheumatology and Immunology, Omaha VA and University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Peter K GregersenThe Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, United States of America.
Timothy BehrensITGR Human Genetics Group, Genentech Inc, San Francisco, California, United States of America.
Soumya RaychaudhuriDivision 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.
Joshua C DennyDepartment of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
Robert M PlengeDivision 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.
Washington University in St. Louis · USMass General Brigham · USUniversity of Manchester · GBBrigham and Women's Hospital · USBroad Institute · USHarvard University · USKarolinska University Hospital · SELeiden University Medical Center · NLNorthwell Health · USRadboud University Nijmegen · NLUniversity of California, Davis · USVanderbilt University · USAmsterdam UMC Location University of Amsterdam · NLAmsterdam UMC Location Vrije Universiteit Amsterdam · NLBicêtre Hospital · FRCenter for Rheumatology · USColumbia University · USHospital de Santa Maria · PTInserm · FRInstituto de Parasitología y Biomedicina "López - Neyra" · ES
Funding
Joint Biology Consortium Resource-based CenterP30AR070253 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI Peter A Nigrovic, Jeffrey Andrew Sparks · 2016 to 2026
$9.4MNovel Biomarkers and Prediction Models for Rheumatoid ArthritisR01AR049880 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI COSTENBADER, KAREN H, KARLSON, ELIZABETH W · 2003 to 2018
$8.7MGenetic predictors of response to anti-TNF therapy in rheumatoid arthritisU01GM092691 · NIGMS · BRIGHAM AND WOMEN'S HOSPITAL · PI BRENNER, MICHAEL B., RAYCHAUDHURI, SOUMYA · 2010 to 2014
$7.5MFrom GWAS to PheWAS: Scanning the EMR Phenome for Gene-disease AssociationsR01LM010685 · NLM · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BASTARACHE, LISA · 2011 to 2022
$6.3MDiscovery and Functional Impact of Common and Rare Variants in RAR01AR063759 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI Soumya Raychaudhuri · 2013 to 2026
$5.4MRA-SLE Molecular Deconstruction Leadership CenterUH2AR067677 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI BRENNER, MICHAEL B., RAYCHAUDHURI, SOUMYA · 2014 to 2020
$4.3MDissection of two rheumatoid arthritis risk loci from genome-wide studiesR01AR056768 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI BRENNER, MICHAEL B. · 2009 to 2013
$1.9MGenetic Risk Factors for Coronary Artery Disease in Rheumatoid ArthritisK08AR060257 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI LIAO, KATHERINE PHOENIX · 2011 to 2015
$649kMeta-analysis of GWAS data to identify novel rheumatoid arthritis risk lociR01AR057108 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI PLENGE, ROBERT M · 2009 to 2010
$557kDeep Re-Sequencing of Rheumatoid Arthritis Risk LociR01AR059648 · NIAMS · BROAD INSTITUTE, INC. · PI PLENGE, ROBERT M · 2010 to 2011
$493kNIAMS NIH HHS K08 AR060257NIAMS NIH HHS P30 AR070253NIAMS NIH HHS R01 AR049880NIAMS NIH HHS R01 AR056768NIAMS NIH HHS R01-AR056768NIAMS NIH HHS R01 AR057108NIAMS NIH HHS R01-AR057108NIAMS NIH HHS R01 AR059648NIAMS NIH HHS R01-AR059648NIAMS NIH HHS R01 AR063759NIAMS NIH HHS R01-AR063759NIAMS NIH HHS UH2 AR067677NIGMS NIH HHS U01 GM092691NIGMS NIH HHS U01-GM092691NLM NIH HHS R01 LM010685
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.
Indexed as
Genetic PleiotropyPolymorphism, Single NucleotideArthritis, RheumatoidAutoimmunityCell Adhesion MoleculesElectronic Health RecordsExonsGenetic LociGenetic Predisposition to DiseaseHumansTYK2 KinaseCell Adhesion MoleculesTYK2 Kinase
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