Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits

Diogo, Dorothée; Bastarache, Lisa; Liao, Katherine P.; Graham, Robert R.; Fulton, Robert S.; Greenberg, Jeffrey D.; Eyre, Steve; Bowes, John; Cui, Jing; Lee, Annette; Pappas, Dimitrios A.; Kremer, Joel M.; Barton, Anne; Coenen, Marieke J. H.; Franke, Barbara; Kiemeney, Lambertus A.; Mariette, Xavier; Richard-Miceli, Corrine; Canhao, Helena; Fonseca, João Eurico; de Vries, Niek; Tak, Paul P.; Crusius, J. Bart A.; Nurmohamed, Michael T.; Kurreeman, Fina; Mikuls, Ted R.; Okada, Yukinori; Stahl, Eli A.; Larson, David E.; Deluca, Tracie L.; O'Laughlin, Michelle; Fronick, Catrina C.; Fulton, Lucinda L.; Kosoy, Roman; Ransom, Michael; Bhangale, Tushar R.; Ortmann, Ward; Cagan, Andrew; Gainer, Vivian; Karlson, Elizabeth W.; Kohane, Isaac; Murphy, Shawn N.; Martin, Javier; Zhernakova, Alexandra; Klareskog, Lars; Padyukov, Leonid; Worthington, Jane; Mardis, Elaine R.; Seldin, Michael F.; Gregersen, Peter K.; Behrens, Timothy; Raychaudhuri, Soumya; Denny, Joshua C.; Plenge, Robert M.

Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits

Detalhes bibliográficos
Autor(a) principal:	Diogo, Dorothée
Data de Publicação:	2015
Outros Autores:	Bastarache, Lisa, Liao, Katherine P., Graham, Robert R., Fulton, Robert S., Greenberg, Jeffrey D., Eyre, Steve, Bowes, John, Cui, Jing, Lee, Annette, Pappas, Dimitrios A., Kremer, Joel M., Barton, Anne, Coenen, Marieke J. H., Franke, Barbara, Kiemeney, Lambertus A., Mariette, Xavier, Richard-Miceli, Corrine, Canhao, Helena, Fonseca, João Eurico, de Vries, Niek, Tak, Paul P., Crusius, J. Bart A., Nurmohamed, Michael T., Kurreeman, Fina, Mikuls, Ted R., Okada, Yukinori, Stahl, Eli A., Larson, David E., Deluca, Tracie L., O'Laughlin, Michelle, Fronick, Catrina C., Fulton, Lucinda L., Kosoy, Roman, Ransom, Michael, Bhangale, Tushar R., Ortmann, Ward, Cagan, Andrew, Gainer, Vivian, Karlson, Elizabeth W., Kohane, Isaac, Murphy, Shawn N., Martin, Javier, Zhernakova, Alexandra, Klareskog, Lars, Padyukov, Leonid, Worthington, Jane, Mardis, Elaine R., Seldin, Michael F., Gregersen, Peter K., Behrens, Timothy, Raychaudhuri, Soumya, Denny, Joshua C., Plenge, Robert M.
Tipo de documento:	Artigo
Idioma:	eng
Título da fonte:	Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo:	http://hdl.handle.net/10451/53176
Resumo:	Copyright: © 2015 Diogo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Metadados do item

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spelling	Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traitsCopyright: © 2015 Diogo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.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.PLoSRepositório da Universidade de LisboaDiogo, DorothéeBastarache, LisaLiao, Katherine P.Graham, Robert R.Fulton, Robert S.Greenberg, Jeffrey D.Eyre, SteveBowes, JohnCui, JingLee, AnnettePappas, Dimitrios A.Kremer, Joel M.Barton, AnneCoenen, Marieke J. H.Franke, BarbaraKiemeney, Lambertus A.Mariette, XavierRichard-Miceli, CorrineCanhao, HelenaFonseca, João Euricode Vries, NiekTak, Paul P.Crusius, J. Bart A.Nurmohamed, Michael T.Kurreeman, FinaMikuls, Ted R.Okada, YukinoriStahl, Eli A.Larson, David E.Deluca, Tracie L.O'Laughlin, MichelleFronick, Catrina C.Fulton, Lucinda L.Kosoy, RomanRansom, MichaelBhangale, Tushar R.Ortmann, WardCagan, AndrewGainer, VivianKarlson, Elizabeth W.Kohane, IsaacMurphy, Shawn N.Martin, JavierZhernakova, AlexandraKlareskog, LarsPadyukov, LeonidWorthington, JaneMardis, Elaine R.Seldin, Michael F.Gregersen, Peter K.Behrens, TimothyRaychaudhuri, SoumyaDenny, Joshua C.Plenge, Robert M.2022-05-25T15:33:49Z20152015-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/53176engPLoS One. 2015 Apr 7;10(4):e012227110.1371/journal.pone.01222711932-6203info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:58:50Zoai:repositorio.ul.pt:10451/53176Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:04:08.774725Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv	Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits
title	Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits
spellingShingle	Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits Diogo, Dorothée
title_short	Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits
title_full	Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits
title_fullStr	Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits
title_full_unstemmed	Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits
title_sort	Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits
author	Diogo, Dorothée
author_facet	Diogo, Dorothée Bastarache, Lisa Liao, Katherine P. Graham, Robert R. Fulton, Robert S. Greenberg, Jeffrey D. Eyre, Steve Bowes, John Cui, Jing Lee, Annette Pappas, Dimitrios A. Kremer, Joel M. Barton, Anne Coenen, Marieke J. H. Franke, Barbara Kiemeney, Lambertus A. Mariette, Xavier Richard-Miceli, Corrine Canhao, Helena Fonseca, João Eurico de Vries, Niek Tak, Paul P. Crusius, J. Bart A. Nurmohamed, Michael T. Kurreeman, Fina Mikuls, Ted R. Okada, Yukinori Stahl, Eli A. Larson, David E. Deluca, Tracie L. O'Laughlin, Michelle Fronick, Catrina C. Fulton, Lucinda L. Kosoy, Roman Ransom, Michael Bhangale, Tushar R. Ortmann, Ward Cagan, Andrew Gainer, Vivian Karlson, Elizabeth W. Kohane, Isaac Murphy, Shawn N. Martin, Javier Zhernakova, Alexandra Klareskog, Lars Padyukov, Leonid Worthington, Jane Mardis, Elaine R. Seldin, Michael F. Gregersen, Peter K. Behrens, Timothy Raychaudhuri, Soumya Denny, Joshua C. Plenge, Robert M.
author_role	author
author2	Bastarache, Lisa Liao, Katherine P. Graham, Robert R. Fulton, Robert S. Greenberg, Jeffrey D. Eyre, Steve Bowes, John Cui, Jing Lee, Annette Pappas, Dimitrios A. Kremer, Joel M. Barton, Anne Coenen, Marieke J. H. Franke, Barbara Kiemeney, Lambertus A. Mariette, Xavier Richard-Miceli, Corrine Canhao, Helena Fonseca, João Eurico de Vries, Niek Tak, Paul P. Crusius, J. Bart A. Nurmohamed, Michael T. Kurreeman, Fina Mikuls, Ted R. Okada, Yukinori Stahl, Eli A. Larson, David E. Deluca, Tracie L. O'Laughlin, Michelle Fronick, Catrina C. Fulton, Lucinda L. Kosoy, Roman Ransom, Michael Bhangale, Tushar R. Ortmann, Ward Cagan, Andrew Gainer, Vivian Karlson, Elizabeth W. Kohane, Isaac Murphy, Shawn N. Martin, Javier Zhernakova, Alexandra Klareskog, Lars Padyukov, Leonid Worthington, Jane Mardis, Elaine R. Seldin, Michael F. Gregersen, Peter K. Behrens, Timothy Raychaudhuri, Soumya Denny, Joshua C. Plenge, Robert M.
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv	Diogo, Dorothée Bastarache, Lisa Liao, Katherine P. Graham, Robert R. Fulton, Robert S. Greenberg, Jeffrey D. Eyre, Steve Bowes, John Cui, Jing Lee, Annette Pappas, Dimitrios A. Kremer, Joel M. Barton, Anne Coenen, Marieke J. H. Franke, Barbara Kiemeney, Lambertus A. Mariette, Xavier Richard-Miceli, Corrine Canhao, Helena Fonseca, João Eurico de Vries, Niek Tak, Paul P. Crusius, J. Bart A. Nurmohamed, Michael T. Kurreeman, Fina Mikuls, Ted R. Okada, Yukinori Stahl, Eli A. Larson, David E. Deluca, Tracie L. O'Laughlin, Michelle Fronick, Catrina C. Fulton, Lucinda L. Kosoy, Roman Ransom, Michael Bhangale, Tushar R. Ortmann, Ward Cagan, Andrew Gainer, Vivian Karlson, Elizabeth W. Kohane, Isaac Murphy, Shawn N. Martin, Javier Zhernakova, Alexandra Klareskog, Lars Padyukov, Leonid Worthington, Jane Mardis, Elaine R. Seldin, Michael F. Gregersen, Peter K. Behrens, Timothy Raychaudhuri, Soumya Denny, Joshua C. Plenge, Robert M.
description	Copyright: © 2015 Diogo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
publishDate	2015
dc.date.none.fl_str_mv	2015 2015-01-01T00:00:00Z 2022-05-25T15:33:49Z
dc.type.status.fl_str_mv	info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv	info:eu-repo/semantics/article
format	article
status_str	publishedVersion
dc.identifier.uri.fl_str_mv	http://hdl.handle.net/10451/53176
url	http://hdl.handle.net/10451/53176
dc.language.iso.fl_str_mv	eng
language	eng
dc.relation.none.fl_str_mv	PLoS One. 2015 Apr 7;10(4):e0122271 10.1371/journal.pone.0122271 1932-6203
dc.rights.driver.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	PLoS
publisher.none.fl_str_mv	PLoS
dc.source.none.fl_str_mv	reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP
instname_str	Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str	RCAAP
institution	RCAAP
reponame_str	Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection	Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv	Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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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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