Genetics of rheumatoid arthritis contributes to biology and drug discovery

Yukinori Okada, Di Wu, Gosia Trynka, Towfique Raj, Chikashi Terao, Katsunori Ikari, Yuta Kochi, Koichiro Ohmura, Akari Suzuki, Shinji Yoshida, Robert R. Graham, Arun Manoharan, Ward Ortmann, Tushar Bhangale, Joshua C. Denny, Robert J. Carroll, Anne E. Eyler, Jeffrey D. Greenberg, Joel M. Kremer, Dimitrios A. PappasLei Jiang, Jian Yin, Lingying Ye, Ding Feng Su, Jian Yang, Gang Xie, Ed Keystone, Harm Jan Westra, Toñu Esko, Andres Metspalu, Xuezhong Zhou, Namrata Gupta, Daniel Mirel, Eli A. Stahl, Dorotheé Diogo, Jing Cui, Katherine Liao, Michael H. Guo, Keiko Myouzen, Takahisa Kawaguchi, Marieke J.H. Coenen, Piet L.C.M. Van Riel, Mart A.F.J. Van De Laar, Henk Jan Guchelaar, Tom W.J. Huizinga, Philippe Dieudé, Xavier Mariette, S. Louis Bridges, Alexandra Zhernakova, Rene E.M. Toes, Paul P. Tak, Corinne Miceli-Richard, So Young Bang, Hye Soon Lee, Javier Martin, Miguel A. Gonzalez-Gay, Luis Rodriguez-Rodriguez, Solbritt Rantapää-Dahlqvist, Lisbeth Ärlestig, Hyon K. Choi, Yoichiro Kamatani, Pilar Galan, Mark Lathrop, Steve Eyre, John Bowes, Anne Barton, Niek De Vries, Larry W. Moreland, Lindsey A. Criswell, Elizabeth W. Karlson, Atsuo Taniguchi, Ryo Yamada, Michiaki Kubo, Jun S. Liu, Sang Cheol Bae, Jane Worthington, Leonid Padyukov, Lars Klareskog, Peter K. Gregersen, Soumya Raychaudhuri, Barbara E. Stranger, Philip L. De Jager, Lude Franke, Peter M. Visscher, Matthew A. Brown, Hisashi Yamanaka, Tsuneyo Mimori, Atsushi Takahashi, Huji Xu, Timothy W. Behrens, Katherine A. Siminovitch, Shigeki Momohara, Fumihiko Matsuda, Kazuhiko Yamamoto, Robert M. Plenge

Research output: Contribution to journalArticle

809 Citations (Scopus)

Abstract

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Original languageEnglish
Pages (from-to)376-381
Number of pages6
JournalNature
Volume506
Issue number7488
DOIs
Publication statusPublished - 07-01-2014

Fingerprint

Drug Discovery
Rheumatoid Arthritis
Genes
Quantitative Trait Loci
Genome-Wide Association Study
Medical Genetics
Computational Biology
Knockout Mice
Computer Simulation
Single Nucleotide Polymorphism
Meta-Analysis
Genome
Phenotype
Mutation
Therapeutics
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • General

Cite this

Okada, Y., Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K., ... Plenge, R. M. (2014). Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature, 506(7488), 376-381. https://doi.org/10.1038/nature12873
Okada, Yukinori ; Wu, Di ; Trynka, Gosia ; Raj, Towfique ; Terao, Chikashi ; Ikari, Katsunori ; Kochi, Yuta ; Ohmura, Koichiro ; Suzuki, Akari ; Yoshida, Shinji ; Graham, Robert R. ; Manoharan, Arun ; Ortmann, Ward ; Bhangale, Tushar ; Denny, Joshua C. ; Carroll, Robert J. ; Eyler, Anne E. ; Greenberg, Jeffrey D. ; Kremer, Joel M. ; Pappas, Dimitrios A. ; Jiang, Lei ; Yin, Jian ; Ye, Lingying ; Su, Ding Feng ; Yang, Jian ; Xie, Gang ; Keystone, Ed ; Westra, Harm Jan ; Esko, Toñu ; Metspalu, Andres ; Zhou, Xuezhong ; Gupta, Namrata ; Mirel, Daniel ; Stahl, Eli A. ; Diogo, Dorotheé ; Cui, Jing ; Liao, Katherine ; Guo, Michael H. ; Myouzen, Keiko ; Kawaguchi, Takahisa ; Coenen, Marieke J.H. ; Van Riel, Piet L.C.M. ; Van De Laar, Mart A.F.J. ; Guchelaar, Henk Jan ; Huizinga, Tom W.J. ; Dieudé, Philippe ; Mariette, Xavier ; Bridges, S. Louis ; Zhernakova, Alexandra ; Toes, Rene E.M. ; Tak, Paul P. ; Miceli-Richard, Corinne ; Bang, So Young ; Lee, Hye Soon ; Martin, Javier ; Gonzalez-Gay, Miguel A. ; Rodriguez-Rodriguez, Luis ; Rantapää-Dahlqvist, Solbritt ; Ärlestig, Lisbeth ; Choi, Hyon K. ; Kamatani, Yoichiro ; Galan, Pilar ; Lathrop, Mark ; Eyre, Steve ; Bowes, John ; Barton, Anne ; De Vries, Niek ; Moreland, Larry W. ; Criswell, Lindsey A. ; Karlson, Elizabeth W. ; Taniguchi, Atsuo ; Yamada, Ryo ; Kubo, Michiaki ; Liu, Jun S. ; Bae, Sang Cheol ; Worthington, Jane ; Padyukov, Leonid ; Klareskog, Lars ; Gregersen, Peter K. ; Raychaudhuri, Soumya ; Stranger, Barbara E. ; De Jager, Philip L. ; Franke, Lude ; Visscher, Peter M. ; Brown, Matthew A. ; Yamanaka, Hisashi ; Mimori, Tsuneyo ; Takahashi, Atsushi ; Xu, Huji ; Behrens, Timothy W. ; Siminovitch, Katherine A. ; Momohara, Shigeki ; Matsuda, Fumihiko ; Yamamoto, Kazuhiko ; Plenge, Robert M. / Genetics of rheumatoid arthritis contributes to biology and drug discovery. In: Nature. 2014 ; Vol. 506, No. 7488. pp. 376-381.
@article{1a1b5694da0348548e299b6768282756,
title = "Genetics of rheumatoid arthritis contributes to biology and drug discovery",
abstract = "A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.",
author = "Yukinori Okada and Di Wu and Gosia Trynka and Towfique Raj and Chikashi Terao and Katsunori Ikari and Yuta Kochi and Koichiro Ohmura and Akari Suzuki and Shinji Yoshida and Graham, {Robert R.} and Arun Manoharan and Ward Ortmann and Tushar Bhangale and Denny, {Joshua C.} and Carroll, {Robert J.} and Eyler, {Anne E.} and Greenberg, {Jeffrey D.} and Kremer, {Joel M.} and Pappas, {Dimitrios A.} and Lei Jiang and Jian Yin and Lingying Ye and Su, {Ding Feng} and Jian Yang and Gang Xie and Ed Keystone and Westra, {Harm Jan} and To{\~n}u Esko and Andres Metspalu and Xuezhong Zhou and Namrata Gupta and Daniel Mirel and Stahl, {Eli A.} and Dorothe{\'e} Diogo and Jing Cui and Katherine Liao and Guo, {Michael H.} and Keiko Myouzen and Takahisa Kawaguchi and Coenen, {Marieke J.H.} and {Van Riel}, {Piet L.C.M.} and {Van De Laar}, {Mart A.F.J.} and Guchelaar, {Henk Jan} and Huizinga, {Tom W.J.} and Philippe Dieud{\'e} and Xavier Mariette and Bridges, {S. Louis} and Alexandra Zhernakova and Toes, {Rene E.M.} and Tak, {Paul P.} and Corinne Miceli-Richard and Bang, {So Young} and Lee, {Hye Soon} and Javier Martin and Gonzalez-Gay, {Miguel A.} and Luis Rodriguez-Rodriguez and Solbritt Rantap{\"a}{\"a}-Dahlqvist and Lisbeth {\"A}rlestig and Choi, {Hyon K.} and Yoichiro Kamatani and Pilar Galan and Mark Lathrop and Steve Eyre and John Bowes and Anne Barton and {De Vries}, Niek and Moreland, {Larry W.} and Criswell, {Lindsey A.} and Karlson, {Elizabeth W.} and Atsuo Taniguchi and Ryo Yamada and Michiaki Kubo and Liu, {Jun S.} and Bae, {Sang Cheol} and Jane Worthington and Leonid Padyukov and Lars Klareskog and Gregersen, {Peter K.} and Soumya Raychaudhuri and Stranger, {Barbara E.} and {De Jager}, {Philip L.} and Lude Franke and Visscher, {Peter M.} and Brown, {Matthew A.} and Hisashi Yamanaka and Tsuneyo Mimori and Atsushi Takahashi and Huji Xu and Behrens, {Timothy W.} and Siminovitch, {Katherine A.} and Shigeki Momohara and Fumihiko Matsuda and Kazuhiko Yamamoto and Plenge, {Robert M.}",
year = "2014",
month = "1",
day = "7",
doi = "10.1038/nature12873",
language = "English",
volume = "506",
pages = "376--381",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7488",

}

Okada, Y, Wu, D, Trynka, G, Raj, T, Terao, C, Ikari, K, Kochi, Y, Ohmura, K, Suzuki, A, Yoshida, S, Graham, RR, Manoharan, A, Ortmann, W, Bhangale, T, Denny, JC, Carroll, RJ, Eyler, AE, Greenberg, JD, Kremer, JM, Pappas, DA, Jiang, L, Yin, J, Ye, L, Su, DF, Yang, J, Xie, G, Keystone, E, Westra, HJ, Esko, T, Metspalu, A, Zhou, X, Gupta, N, Mirel, D, Stahl, EA, Diogo, D, Cui, J, Liao, K, Guo, MH, Myouzen, K, Kawaguchi, T, Coenen, MJH, Van Riel, PLCM, Van De Laar, MAFJ, Guchelaar, HJ, Huizinga, TWJ, Dieudé, P, Mariette, X, Bridges, SL, Zhernakova, A, Toes, REM, Tak, PP, Miceli-Richard, C, Bang, SY, Lee, HS, Martin, J, Gonzalez-Gay, MA, Rodriguez-Rodriguez, L, Rantapää-Dahlqvist, S, Ärlestig, L, Choi, HK, Kamatani, Y, Galan, P, Lathrop, M, Eyre, S, Bowes, J, Barton, A, De Vries, N, Moreland, LW, Criswell, LA, Karlson, EW, Taniguchi, A, Yamada, R, Kubo, M, Liu, JS, Bae, SC, Worthington, J, Padyukov, L, Klareskog, L, Gregersen, PK, Raychaudhuri, S, Stranger, BE, De Jager, PL, Franke, L, Visscher, PM, Brown, MA, Yamanaka, H, Mimori, T, Takahashi, A, Xu, H, Behrens, TW, Siminovitch, KA, Momohara, S, Matsuda, F, Yamamoto, K & Plenge, RM 2014, 'Genetics of rheumatoid arthritis contributes to biology and drug discovery', Nature, vol. 506, no. 7488, pp. 376-381. https://doi.org/10.1038/nature12873

Genetics of rheumatoid arthritis contributes to biology and drug discovery. / Okada, Yukinori; Wu, Di; Trynka, Gosia; Raj, Towfique; Terao, Chikashi; Ikari, Katsunori; Kochi, Yuta; Ohmura, Koichiro; Suzuki, Akari; Yoshida, Shinji; Graham, Robert R.; Manoharan, Arun; Ortmann, Ward; Bhangale, Tushar; Denny, Joshua C.; Carroll, Robert J.; Eyler, Anne E.; Greenberg, Jeffrey D.; Kremer, Joel M.; Pappas, Dimitrios A.; Jiang, Lei; Yin, Jian; Ye, Lingying; Su, Ding Feng; Yang, Jian; Xie, Gang; Keystone, Ed; Westra, Harm Jan; Esko, Toñu; Metspalu, Andres; Zhou, Xuezhong; Gupta, Namrata; Mirel, Daniel; Stahl, Eli A.; Diogo, Dorotheé; Cui, Jing; Liao, Katherine; Guo, Michael H.; Myouzen, Keiko; Kawaguchi, Takahisa; Coenen, Marieke J.H.; Van Riel, Piet L.C.M.; Van De Laar, Mart A.F.J.; Guchelaar, Henk Jan; Huizinga, Tom W.J.; Dieudé, Philippe; Mariette, Xavier; Bridges, S. Louis; Zhernakova, Alexandra; Toes, Rene E.M.; Tak, Paul P.; Miceli-Richard, Corinne; Bang, So Young; Lee, Hye Soon; Martin, Javier; Gonzalez-Gay, Miguel A.; Rodriguez-Rodriguez, Luis; Rantapää-Dahlqvist, Solbritt; Ärlestig, Lisbeth; Choi, Hyon K.; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Eyre, Steve; Bowes, John; Barton, Anne; De Vries, Niek; Moreland, Larry W.; Criswell, Lindsey A.; Karlson, Elizabeth W.; Taniguchi, Atsuo; Yamada, Ryo; Kubo, Michiaki; Liu, Jun S.; Bae, Sang Cheol; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Gregersen, Peter K.; Raychaudhuri, Soumya; Stranger, Barbara E.; De Jager, Philip L.; Franke, Lude; Visscher, Peter M.; Brown, Matthew A.; Yamanaka, Hisashi; Mimori, Tsuneyo; Takahashi, Atsushi; Xu, Huji; Behrens, Timothy W.; Siminovitch, Katherine A.; Momohara, Shigeki; Matsuda, Fumihiko; Yamamoto, Kazuhiko; Plenge, Robert M.

In: Nature, Vol. 506, No. 7488, 07.01.2014, p. 376-381.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetics of rheumatoid arthritis contributes to biology and drug discovery

AU - Okada, Yukinori

AU - Wu, Di

AU - Trynka, Gosia

AU - Raj, Towfique

AU - Terao, Chikashi

AU - Ikari, Katsunori

AU - Kochi, Yuta

AU - Ohmura, Koichiro

AU - Suzuki, Akari

AU - Yoshida, Shinji

AU - Graham, Robert R.

AU - Manoharan, Arun

AU - Ortmann, Ward

AU - Bhangale, Tushar

AU - Denny, Joshua C.

AU - Carroll, Robert J.

AU - Eyler, Anne E.

AU - Greenberg, Jeffrey D.

AU - Kremer, Joel M.

AU - Pappas, Dimitrios A.

AU - Jiang, Lei

AU - Yin, Jian

AU - Ye, Lingying

AU - Su, Ding Feng

AU - Yang, Jian

AU - Xie, Gang

AU - Keystone, Ed

AU - Westra, Harm Jan

AU - Esko, Toñu

AU - Metspalu, Andres

AU - Zhou, Xuezhong

AU - Gupta, Namrata

AU - Mirel, Daniel

AU - Stahl, Eli A.

AU - Diogo, Dorotheé

AU - Cui, Jing

AU - Liao, Katherine

AU - Guo, Michael H.

AU - Myouzen, Keiko

AU - Kawaguchi, Takahisa

AU - Coenen, Marieke J.H.

AU - Van Riel, Piet L.C.M.

AU - Van De Laar, Mart A.F.J.

AU - Guchelaar, Henk Jan

AU - Huizinga, Tom W.J.

AU - Dieudé, Philippe

AU - Mariette, Xavier

AU - Bridges, S. Louis

AU - Zhernakova, Alexandra

AU - Toes, Rene E.M.

AU - Tak, Paul P.

AU - Miceli-Richard, Corinne

AU - Bang, So Young

AU - Lee, Hye Soon

AU - Martin, Javier

AU - Gonzalez-Gay, Miguel A.

AU - Rodriguez-Rodriguez, Luis

AU - Rantapää-Dahlqvist, Solbritt

AU - Ärlestig, Lisbeth

AU - Choi, Hyon K.

AU - Kamatani, Yoichiro

AU - Galan, Pilar

AU - Lathrop, Mark

AU - Eyre, Steve

AU - Bowes, John

AU - Barton, Anne

AU - De Vries, Niek

AU - Moreland, Larry W.

AU - Criswell, Lindsey A.

AU - Karlson, Elizabeth W.

AU - Taniguchi, Atsuo

AU - Yamada, Ryo

AU - Kubo, Michiaki

AU - Liu, Jun S.

AU - Bae, Sang Cheol

AU - Worthington, Jane

AU - Padyukov, Leonid

AU - Klareskog, Lars

AU - Gregersen, Peter K.

AU - Raychaudhuri, Soumya

AU - Stranger, Barbara E.

AU - De Jager, Philip L.

AU - Franke, Lude

AU - Visscher, Peter M.

AU - Brown, Matthew A.

AU - Yamanaka, Hisashi

AU - Mimori, Tsuneyo

AU - Takahashi, Atsushi

AU - Xu, Huji

AU - Behrens, Timothy W.

AU - Siminovitch, Katherine A.

AU - Momohara, Shigeki

AU - Matsuda, Fumihiko

AU - Yamamoto, Kazuhiko

AU - Plenge, Robert M.

PY - 2014/1/7

Y1 - 2014/1/7

N2 - A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

AB - A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

UR - http://www.scopus.com/inward/record.url?scp=84894288992&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894288992&partnerID=8YFLogxK

U2 - 10.1038/nature12873

DO - 10.1038/nature12873

M3 - Article

C2 - 24390342

AN - SCOPUS:84894288992

VL - 506

SP - 376

EP - 381

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7488

ER -

Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014 Jan 7;506(7488):376-381. https://doi.org/10.1038/nature12873