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, Tonu Esko, Andres Metspalu, Xuezhong Zhou, Namrata Gupta, Daniel Mirel, Eli A Stahl, Dorothee 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 Dieude, Xavier Mariette, S Louis Bridges Jr, 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 Rantapaa-Dahlqvi, Lisbeth Arlestig, Hyon K Choi, Yoichiro Kamatani, Pilar Galan, Mark Lathrop, Annette Lee, Paul Martin, Eli Stah, Sebastien Viatte, Kate McAllister, Christopher I Amos, Cisca Wijmenga, Lars Alfredsson, Xinli Hu, Cynthia Sandor, Paul I W de Bakker, Sonia Davila, Chiea Chuen Khor, Khai Koon Heng, Robert Andrews, Sarah Edkins, Sarah E Hunt, Cordelia Langford, Deborah Symmons, Patrick Concannon, Suna Onengut-Gumuscu, Stephen Rich, Panos Deloukas, Lisbeth Arlsetig, Fina Kurreman, Nao Nishida, Hiroko Ohmiya, Meiko Takahashi, Tetsuji Sawada, Yuichi Nishioka, Masao Yukioka, Tsukasa Matsubara, Shigeyuki Wakitani, Ryota Teshima, Shigeto Tohma, Kiyoshi Takasugi, Kota Shimada, Akira Murasawa, Shigeru Honjo, Keitaro Matsuo, Hideo Tanaka, Kazuo Tajima, Taku Suzuki, Takuji Iwamot, Yoshiya Kawamura, Hisashi Tanii, Yuji Okazaki, Tsukasa Sasaki, Katsushi Tokunaga, Yusuke Nakamura, Naoyuki Kamatani, Steve Eyre, John Bowes, Anne Barton, Niek de Vries, Larry W Moreland, Lindsey 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 journalArticleResearchpeer-review

871 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 approximately 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 - 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 - 2014

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, Tonu ; Metspalu, Andres ; Zhou, Xuezhong ; Gupta, Namrata ; Mirel, Daniel ; Stahl, Eli A ; Diogo, Dorothee ; 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 ; Dieude, Philippe ; Mariette, Xavier ; Bridges Jr, 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 ; Rantapaa-Dahlqvi, Solbritt ; Arlestig, Lisbeth ; Choi, Hyon K ; Kamatani, Yoichiro ; Galan, Pilar ; Lathrop, Mark ; Lee, Annette ; Martin, Paul ; Stah, Eli ; Viatte, Sebastien ; McAllister, Kate ; Amos, Christopher I ; Wijmenga, Cisca ; Alfredsson, Lars ; Hu, Xinli ; Sandor, Cynthia ; de Bakker, Paul I W ; Davila, Sonia ; Khor, Chiea Chuen ; Heng, Khai Koon ; Andrews, Robert ; Edkins, Sarah ; Hunt, Sarah E ; Langford, Cordelia ; Symmons, Deborah ; Concannon, Patrick ; Onengut-Gumuscu, Suna ; Rich, Stephen ; Deloukas, Panos ; Arlsetig, Lisbeth ; Kurreman, Fina ; Nishida, Nao ; Ohmiya, Hiroko ; Takahashi, Meiko ; Sawada, Tetsuji ; Nishioka, Yuichi ; Yukioka, Masao ; Matsubara, Tsukasa ; Wakitani, Shigeyuki ; Teshima, Ryota ; Tohma, Shigeto ; Takasugi, Kiyoshi ; Shimada, Kota ; Murasawa, Akira ; Honjo, Shigeru ; Matsuo, Keitaro ; Tanaka, Hideo ; Tajima, Kazuo ; Suzuki, Taku ; Iwamot, Takuji ; Kawamura, Yoshiya ; Tanii, Hisashi ; Okazaki, Yuji ; Sasaki, Tsukasa ; Tokunaga, Katsushi ; Nakamura, Yusuke ; Kamatani, Naoyuki ; Eyre, Steve ; Bowes, John ; Barton, Anne ; de Vries, Niek ; Moreland, Larry W ; Criswell, Lindsey ; 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.
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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 approximately 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 - 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 Ding-Feng Su and Jian Yang and Gang Xie and Ed Keystone and Harm-Jan Westra and Tonu Esko and Andres Metspalu and Xuezhong Zhou and Namrata Gupta and Daniel Mirel and Stahl, {Eli A} and Dorothee 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 Henk-Jan Guchelaar and Huizinga, {Tom W J} and Philippe Dieude and Xavier Mariette and {Bridges Jr}, {S Louis} and Alexandra Zhernakova and Toes, {Rene E M} and Tak, {Paul P} and Corinne Miceli-Richard and So-Young Bang and Hye-Soon Lee and Javier Martin and Gonzalez-Gay, {Miguel A} and Luis Rodriguez-Rodriguez and Solbritt Rantapaa-Dahlqvi and Lisbeth Arlestig and Choi, {Hyon K} and Yoichiro Kamatani and Pilar Galan and Mark Lathrop and Annette Lee and Paul Martin and Eli Stah and Sebastien Viatte and Kate McAllister and Amos, {Christopher I} and Cisca Wijmenga and Lars Alfredsson and Xinli Hu and Cynthia Sandor and {de Bakker}, {Paul I W} and Sonia Davila and Khor, {Chiea Chuen} and Heng, {Khai Koon} and Robert Andrews and Sarah Edkins and Hunt, {Sarah E} and Cordelia Langford and Deborah Symmons and Patrick Concannon and Suna Onengut-Gumuscu and Stephen Rich and Panos Deloukas and Lisbeth Arlsetig and Fina Kurreman and Nao Nishida and Hiroko Ohmiya and Meiko Takahashi and Tetsuji Sawada and Yuichi Nishioka and Masao Yukioka and Tsukasa Matsubara and Shigeyuki Wakitani and Ryota Teshima and Shigeto Tohma and Kiyoshi Takasugi and Kota Shimada and Akira Murasawa and Shigeru Honjo and Keitaro Matsuo and Hideo Tanaka and Kazuo Tajima and Taku Suzuki and Takuji Iwamot and Yoshiya Kawamura and Hisashi Tanii and Yuji Okazaki and Tsukasa Sasaki and Katsushi Tokunaga and Yusuke Nakamura and Naoyuki Kamatani and Steve Eyre and John Bowes and Anne Barton and {de Vries}, Niek and Moreland, {Larry W} and Lindsey Criswell and Karlson, {Elizabeth W} and Atsuo Taniguchi and Ryo Yamada and Michiaki Kubo and Liu, {Jun S} and Sang-Cheol Bae 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",
doi = "10.1038/nature12873",
language = "English",
volume = "506",
pages = "376 -- 381",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7488",

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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, D-F, Yang, J, Xie, G, Keystone, E, Westra, H-J, 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, H-J, Huizinga, TWJ, Dieude, P, Mariette, X, Bridges Jr, SL, Zhernakova, A, Toes, REM, Tak, PP, Miceli-Richard, C, Bang, S-Y, Lee, H-S, Martin, J, Gonzalez-Gay, MA, Rodriguez-Rodriguez, L, Rantapaa-Dahlqvi, S, Arlestig, L, Choi, HK, Kamatani, Y, Galan, P, Lathrop, M, Lee, A, Martin, P, Stah, E, Viatte, S, McAllister, K, Amos, CI, Wijmenga, C, Alfredsson, L, Hu, X, Sandor, C, de Bakker, PIW, Davila, S, Khor, CC, Heng, KK, Andrews, R, Edkins, S, Hunt, SE, Langford, C, Symmons, D, Concannon, P, Onengut-Gumuscu, S, Rich, S, Deloukas, P, Arlsetig, L, Kurreman, F, Nishida, N, Ohmiya, H, Takahashi, M, Sawada, T, Nishioka, Y, Yukioka, M, Matsubara, T, Wakitani, S, Teshima, R, Tohma, S, Takasugi, K, Shimada, K, Murasawa, A, Honjo, S, Matsuo, K, Tanaka, H, Tajima, K, Suzuki, T, Iwamot, T, Kawamura, Y, Tanii, H, Okazaki, Y, Sasaki, T, Tokunaga, K, Nakamura, Y, Kamatani, N, Eyre, S, Bowes, J, Barton, A, de Vries, N, Moreland, LW, Criswell, L, Karlson, EW, Taniguchi, A, Yamada, R, Kubo, M, Liu, JS, Bae, S-C, 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, Tonu; Metspalu, Andres; Zhou, Xuezhong; Gupta, Namrata; Mirel, Daniel; Stahl, Eli A; Diogo, Dorothee; 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; Dieude, Philippe; Mariette, Xavier; Bridges Jr, 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; Rantapaa-Dahlqvi, Solbritt; Arlestig, Lisbeth; Choi, Hyon K; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Lee, Annette; Martin, Paul; Stah, Eli; Viatte, Sebastien; McAllister, Kate; Amos, Christopher I; Wijmenga, Cisca; Alfredsson, Lars; Hu, Xinli; Sandor, Cynthia; de Bakker, Paul I W; Davila, Sonia; Khor, Chiea Chuen; Heng, Khai Koon; Andrews, Robert; Edkins, Sarah; Hunt, Sarah E; Langford, Cordelia; Symmons, Deborah; Concannon, Patrick; Onengut-Gumuscu, Suna; Rich, Stephen; Deloukas, Panos; Arlsetig, Lisbeth; Kurreman, Fina; Nishida, Nao; Ohmiya, Hiroko; Takahashi, Meiko; Sawada, Tetsuji; Nishioka, Yuichi; Yukioka, Masao; Matsubara, Tsukasa; Wakitani, Shigeyuki; Teshima, Ryota; Tohma, Shigeto; Takasugi, Kiyoshi; Shimada, Kota; Murasawa, Akira; Honjo, Shigeru; Matsuo, Keitaro; Tanaka, Hideo; Tajima, Kazuo; Suzuki, Taku; Iwamot, Takuji; Kawamura, Yoshiya; Tanii, Hisashi; Okazaki, Yuji; Sasaki, Tsukasa; Tokunaga, Katsushi; Nakamura, Yusuke; Kamatani, Naoyuki; Eyre, Steve; Bowes, John; Barton, Anne; de Vries, Niek; Moreland, Larry W; Criswell, Lindsey; 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, 2014, p. 376 - 381.

Research output: Contribution to journalArticleResearchpeer-review

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, Tonu

AU - Metspalu, Andres

AU - Zhou, Xuezhong

AU - Gupta, Namrata

AU - Mirel, Daniel

AU - Stahl, Eli A

AU - Diogo, Dorothee

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 - Dieude, Philippe

AU - Mariette, Xavier

AU - Bridges Jr, 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 - Rantapaa-Dahlqvi, Solbritt

AU - Arlestig, Lisbeth

AU - Choi, Hyon K

AU - Kamatani, Yoichiro

AU - Galan, Pilar

AU - Lathrop, Mark

AU - Lee, Annette

AU - Martin, Paul

AU - Stah, Eli

AU - Viatte, Sebastien

AU - McAllister, Kate

AU - Amos, Christopher I

AU - Wijmenga, Cisca

AU - Alfredsson, Lars

AU - Hu, Xinli

AU - Sandor, Cynthia

AU - de Bakker, Paul I W

AU - Davila, Sonia

AU - Khor, Chiea Chuen

AU - Heng, Khai Koon

AU - Andrews, Robert

AU - Edkins, Sarah

AU - Hunt, Sarah E

AU - Langford, Cordelia

AU - Symmons, Deborah

AU - Concannon, Patrick

AU - Onengut-Gumuscu, Suna

AU - Rich, Stephen

AU - Deloukas, Panos

AU - Arlsetig, Lisbeth

AU - Kurreman, Fina

AU - Nishida, Nao

AU - Ohmiya, Hiroko

AU - Takahashi, Meiko

AU - Sawada, Tetsuji

AU - Nishioka, Yuichi

AU - Yukioka, Masao

AU - Matsubara, Tsukasa

AU - Wakitani, Shigeyuki

AU - Teshima, Ryota

AU - Tohma, Shigeto

AU - Takasugi, Kiyoshi

AU - Shimada, Kota

AU - Murasawa, Akira

AU - Honjo, Shigeru

AU - Matsuo, Keitaro

AU - Tanaka, Hideo

AU - Tajima, Kazuo

AU - Suzuki, Taku

AU - Iwamot, Takuji

AU - Kawamura, Yoshiya

AU - Tanii, Hisashi

AU - Okazaki, Yuji

AU - Sasaki, Tsukasa

AU - Tokunaga, Katsushi

AU - Nakamura, Yusuke

AU - Kamatani, Naoyuki

AU - Eyre, Steve

AU - Bowes, John

AU - Barton, Anne

AU - de Vries, Niek

AU - Moreland, Larry W

AU - Criswell, Lindsey

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

Y1 - 2014

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 approximately 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 - 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 approximately 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 - 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.nature.com/nature/journal/v506/n7488/pdf/nature12873.pdf

U2 - 10.1038/nature12873

DO - 10.1038/nature12873

M3 - Article

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;506(7488):376 - 381. https://doi.org/10.1038/nature12873