TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits

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

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 pro-tein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3×10-21), A928V (rs35018800, OR = 0.53, P = 1.2×10-9), and I684S (rs12720356, OR = 0.86, P = 4.6×10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6×10-18 ), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide 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.

Original languageEnglish (US)
Article numbere0122271
JournalPLoS One
Volume10
Issue number4
DOIs
StatePublished - Apr 7 2015
Externally publishedYes

Fingerprint

Focal Adhesion Kinase 1
TYK2 Kinase
autoimmunity
rheumatoid arthritis
Autoimmunity
tyrosine
Rheumatoid Arthritis
phosphotransferases (kinases)
Genes
autoimmune diseases
Genome-Wide Association Study
Phenotype
phenotype
proteins
genotyping
Autoimmune Diseases
Electronic medical equipment
lupus erythematosus
loci
Electronic Health Records

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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; Canhão, Helena; Fonseca, João E.; 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.

In: PLoS One, Vol. 10, No. 4, e0122271, 07.04.2015.

Research output: Contribution to journalArticle

Diogo, D, Bastarache, L, Liao, KP, Graham, RR, Fulton, RS, Greenberg, JD, Eyre, S, Bowes, J, Cui, J, Lee, A, Pappas, DA, Kremer, JM, Barton, A, Coenen, MJH, Franke, B, Kiemeney, LA, Mariette, X, Richard-Miceli, C, Canhão, H, Fonseca, JE, De Vries, N, Tak, PP, Crusius, JBA, Nurmohamed, MT, Kurreeman, F, Mikuls, TR, Okada, Y, Stahl, EA, Larson, DE, Deluca, TL, O'Laughlin, M, Fronick, CC, Fulton, LL, Kosoy, R, Ransom, M, Bhangale, TR, Ortmann, W, Cagan, A, Gainer, V, Karlson, EW, Kohane, I, Murphy, SN, Martin, J, Zhernakova, A, Klareskog, L, Padyukov, L, Worthington, J, Mardis, ER, Seldin, MF, Gregersen, PK, Behrens, T, Raychaudhuri, S, Denny, JC & Plenge, RM 2015, 'TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits', PLoS One, vol. 10, no. 4, e0122271. https://doi.org/10.1371/journal.pone.0122271
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 ; Canhão, Helena ; Fonseca, João E. ; 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. In: PLoS One. 2015 ; Vol. 10, No. 4.
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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 pro-tein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3×10-21), A928V (rs35018800, OR = 0.53, P = 1.2×10-9), and I684S (rs12720356, OR = 0.86, P = 4.6×10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6×10-18 ), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide 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.",
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TY - JOUR

T1 - TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits

AU - Diogo, Dorothée

AU - Bastarache, Lisa

AU - Liao, Katherine P.

AU - Graham, Robert R.

AU - Fulton, Robert S.

AU - Greenberg, Jeffrey D.

AU - Eyre, Steve

AU - Bowes, John

AU - Cui, Jing

AU - Lee, Annette

AU - Pappas, Dimitrios A.

AU - Kremer, Joel M.

AU - Barton, Anne

AU - Coenen, Marieke J H

AU - Franke, Barbara

AU - Kiemeney, Lambertus A.

AU - Mariette, Xavier

AU - Richard-Miceli, Corrine

AU - Canhão, Helena

AU - Fonseca, João E.

AU - De Vries, Niek

AU - Tak, Paul P.

AU - Crusius, J. Bart A

AU - Nurmohamed, Michael T.

AU - Kurreeman, Fina

AU - Mikuls, Ted R.

AU - Okada, Yukinori

AU - Stahl, Eli A.

AU - Larson, David E.

AU - Deluca, Tracie L.

AU - O'Laughlin, Michelle

AU - Fronick, Catrina C.

AU - Fulton, Lucinda L.

AU - Kosoy, Roman

AU - Ransom, Michael

AU - Bhangale, Tushar R.

AU - Ortmann, Ward

AU - Cagan, Andrew

AU - Gainer, Vivian

AU - Karlson, Elizabeth W.

AU - Kohane, Isaac

AU - Murphy, Shawn N.

AU - Martin, Javier

AU - Zhernakova, Alexandra

AU - Klareskog, Lars

AU - Padyukov, Leonid

AU - Worthington, Jane

AU - Mardis, Elaine R.

AU - Seldin, Michael F

AU - Gregersen, Peter K.

AU - Behrens, Timothy

AU - Raychaudhuri, Soumya

AU - Denny, Joshua C.

AU - Plenge, Robert M.

PY - 2015/4/7

Y1 - 2015/4/7

N2 - 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 pro-tein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3×10-21), A928V (rs35018800, OR = 0.53, P = 1.2×10-9), and I684S (rs12720356, OR = 0.86, P = 4.6×10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6×10-18 ), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide 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.

AB - 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 pro-tein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3×10-21), A928V (rs35018800, OR = 0.53, P = 1.2×10-9), and I684S (rs12720356, OR = 0.86, P = 4.6×10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6×10-18 ), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide 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.

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