Genetics of rheumatoid arthritis contributes to biology and drug discovery
Yukinori Okada,Yukinori Okada,Di Wu,Di Wu,Di Wu,Gosia Trynka,Gosia Trynka,Towfique Raj,Towfique Raj,Chikashi Terao,Katsunori Ikari,Yuta Kochi,Koichiro Ohmura,Akari Suzuki,Shinji Yoshida,Robert R. Graham,A. Manoharan,Ward Ortmann,Tushar Bhangale,Joshua C. Denny,Robert J. Carroll,Anne E. Eyler,Jeff Greenberg,Joel M. Kremer,Dimitrios A. Pappas,Lei Jiang,Jian Yin,Lingying Ye,Ding Feng Su,Jian Yang,Gang Xie,E.C. Keystone,Harm-Jan Westra,Tõnu Esko,Tõnu Esko,Tõnu Esko,Andres Metspalu,Xuezhong Zhou,Namrata Gupta,Daniel B. Mirel,Eli A. Stahl,Dorothee Diogo,Dorothee Diogo,Jing Cui,Jing Cui,Katherine P. Liao,Katherine P. Liao,Michael H. Guo,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,Alexandra Zhernakova,René E. M. Toes,Paul P. Tak,Paul P. Tak,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,Hyon K. Choi,Yoichiro Kamatani,Pilar Galan,Mark Lathrop,Steve Eyre,Steve Eyre,John Bowes,John Bowes,Anne Barton,Niek de Vries,Larry W. Moreland,Lindsey A. Criswell,Elizabeth W. Karlson,Atsuo Taniguchi,Ryo Yamada,Michiaki Kubo,Jun Liu,Sang Cheol Bae,Jane Worthington,Jane Worthington,Leonid Padyukov,Lars Klareskog,Peter K. Gregersen,Soumya Raychaudhuri,Soumya Raychaudhuri,Barbara E. Stranger,Philip L. De Jager,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,Robert M. Plenge +115 more
TLDR
A genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries provides empirical evidence that the genetics of RA can provide important information for drug discovery, and sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis.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)1. 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 annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—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.read more
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10 Years of GWAS Discovery: Biology, Function, and Translation
Peter M. Visscher,Naomi R. Wray,Qian Zhang,Pamela Sklar,Mark I. McCarthy,Matthew A. Brown,Jian Yang +6 more
TL;DR: The remarkable range of discoveriesGWASs has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics are reviewed.
Journal ArticleDOI
An Expanded View of Complex Traits: From Polygenic to Omnigenic
TL;DR: It is proposed that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and that most heritability can be explained by effects on genes outside core pathways.
Journal ArticleDOI
Partitioning heritability by functional annotation using genome-wide association summary statistics.
Hilary K. Finucane,Hilary K. Finucane,Brendan Bulik-Sullivan,Brendan Bulik-Sullivan,Alexander Gusev,Gosia Trynka,Yakir A. Reshef,Po-Ru Loh,Verneri Anttila,Verneri Anttila,Han Xu,Chongzhi Zang,Kyle Kai-How Farh,Kyle Kai-How Farh,Stephan Ripke,Stephan Ripke,Felix R. Day,Shaun Purcell,Shaun Purcell,Eli A. Stahl,Sara Lindström,John R. B. Perry,Yukinori Okada,Soumya Raychaudhuri,Mark J. Daly,Mark J. Daly,Nick Patterson,Benjamin M. Neale,Benjamin M. Neale,Alkes L. Price,Alkes L. Price +30 more
TL;DR: A new method is introduced, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers, which is computationally tractable at very large sample sizes and leverages genome-wide information.
Journal ArticleDOI
Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations
Jimmy Z. Liu,S van Sommeren,Hailiang Huang,Siew C. Ng,Rudi Alberts,Atsushi Takahashi,Stephan Ripke,James Lee,Luke Jostins,Tejas Shah,Shifteh Abedian,Jae Hee Cheon,Judy H. Cho,N E Dayani,Lude Franke,Yuta Fuyuno,Ailsa L. Hart,Ramesh C. Juyal,Garima Juyal,Won Ho Kim,Andrew P. Morris,Hossein Poustchi,William G. Newman,Vandana Midha,Timothy R. Orchard,H Vahedi,Ajit Sood,J Y Sung,Reza Malekzadeh,Westra H-J.,Keiko Yamazaki,Yang S-K.,Jeffrey C. Barrett,Behrooz Z. Alizadeh,Miles Parkes,T Bk,Mark J. Daly,Michiaki Kubo,Carl A. Anderson,Rinse K. Weersma +39 more
TL;DR: The first trans-ancestry association study of IBD is reported, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent, implicate 38 loci in IBD risk for the first time.
Journal ArticleDOI
The GTEx Consortium atlas of genetic regulatory effects across human tissues
François Aguet,Alvaro N. Barbeira,Rodrigo Bonazzola,Andrew A. Brown,SE Castel,Brian Jo,Silva Kasela,Sarah Kim-Hellmuth,Yanyu Liang,Meritxell Oliva,Elise D. Flynn,Princy Parsana,Laure Fresard,Eric R. Gamazon,Andrew R. Hamel,Yuan He,Farhad Hormozdiari,Pejman Mohammadi,Manuel Muñoz-Aguirre,YoSon Park,Ashis Saha,Ayellet V. Segrè,Benjamin J. Strober,Xiaoquan Wen,Wucher,Kristin G. Ardlie,Alexis Battle,Christopher D. Brown,Nancy J. Cox,Souvik Das,Emmanouil T. Dermitzakis,Barbara E. Engelhardt,D Garrido-Martin,Gad Getz,Roderic Guigó,Robert E. Handsaker,Paul J. Hoffman,Hae Kyung Im,Seva Kashin,Alan Kwong,Lappalainen T,Xiao Li,Daniel G. MacArthur,Stephen B. Montgomery,John M. Rouhana,Matthew Stephens,Barbara E. Stranger,Ellen Todres,Ana Viñuela,Gao Wang,Yuxin Zou,Shankara Anand,S. Gabriel,Aaron Graubert,Kane Hadley,Katherine H. Huang,Meier,Jared L. Nedzel,Duyen T. Nguyen,Brunilda Balliu,Donald F. Conrad,Daniel J. Cotter,OM deGoede,Jonah Einson,Eskin E,Tiffany Eulalio,Nicole M. Ferraro,Michael J. Gloudemans,Lei Hou,Serghei Mangul,Daniel Nachun,Andrew B. Nobel,Abhiram Rao,Ferran Reverter,Chiara Sabatti,Andrew D Skol,Nicole A. Teran,Fred A. Wright,Pedro G. Ferreira,Gen Li,Marta Melé,Esti Yeger-Lotem,Mary Barcus,Debra Bradbury,T Krubit,Jeffrey McLean,Liqun Qi,Karna Robinson,Nancy Roche,Anna M. Smith,David E. Tabor,Anita H. Undale,Jason Bridge,Lori E. Brigham,Barbara A. Foster,Bryan Gillard,Rick Hasz,Marcus Hunter,Christopher Johns,Mark H. Johnson,Ellen Karasik,Gene Kopen,William F. Leinweber,Alisa McDonald,Mike Moser,Kevin Myer,Kimberly Ramsey,Bruce A. Roe,Saboor Shad,Jeffrey A. Thomas,Gary Walters,Michael Washington,Jessica Wheeler,Scott D. Jewell,Daniel C. Rohrer,David A. Davis,Deborah C. Mash,Leslie H. Sobin,Laura Barker,HM Gardiner,Maghboeba Mosavel,Laura A. Siminoff,Paul Flicek,Maximilian Haeussler,Thomas Juettemann,W. J. Kent,Christopher Lee,CC Powell,Kate R. Rosenbloom,Magali Ruffier,Dan Sheppard,Kieron Taylor,Stephen J. Trevanion,Zerbino,Nathan S. Abell,Joshua M. Akey,Lin Chen,Kathryn Demanelis,Jennifer A. Doherty,Andrew P. Feinberg,Kasper D. Hansen,Peter Hickey,Farzana Jasmine,Lihua Jiang,Rajinder Kaul,Manolis Kellis,Muhammad G. Kibriya,Jin Billy Li,Qin Li,Shin Lin,Sandra Linder,Brandon L. Pierce,Lindsay F. Rizzardi,Kevin S. Smith,Michael Snyder,John A. Stamatoyannopoulos,Hua Tang,Meng Wang,Phillip Branton,Latarsha J. Carithers,Ping Guan,Susan E. Koester,AR Little,Helen M. Moore,Concepcion R. Nierras,Abhi Rao,Jimmie B. Vaught,Simona Volpi +167 more
References
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Journal ArticleDOI
The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.
Frank C. Arnett,Steven M. Edworthy,Daniel A. Bloch,Dennis J. McShane,James F. Fries,Norman S. Cooper,L. A. Healey,Stephen R. Kaplan,Matthew H. Liang,Harvinder S. Luthra,Thomas A. Medsger,Donald M. Mitchell,David H. Neustadt,Robert S. Pinals,Jane G. Schaller,John T. Sharp,Ronald L. Wilder,Gene G. Hunder +17 more
TL;DR: The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA).
Journal Article
Revised criteria for the classification of rheumatoid arthritis.
TL;DR: The Bulletin on the Rheumatic Diseases has published all of the classification criteria for the rheumatic diseases to date, and these new revised classified criteria for rheumatoid arthritis are very important as they should provide understanding of the possibly changing face of rheumatism.
Journal ArticleDOI
An integrated map of genetic variation from 1,092 human genomes
Gonçalo R. Abecasis,Adam Auton,Lisa D. Brooks,Mark A. DePristo,Richard Durbin,Robert E. Handsaker,Robert E. Handsaker,Hyun Min Kang,Gabor T. Marth,Gil McVean +9 more
TL;DR: It is shown that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites.
Journal ArticleDOI
Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
Lucia A. Hindorff,Praveen Sethupathy,Heather Junkins,Erin M. Ramos,Jayashri P. Mehta,Francis S. Collins,Teri A. Manolio +6 more
TL;DR: An online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs) is developed, well-suited to guide future investigations of the role of common variants in complex disease etiology.
Journal ArticleDOI
The pathogenesis of rheumatoid arthritis.
Iain B. McInnes,Georg Schett +1 more
TL;DR: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
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Welch,Mary Kate Wing,Xiaowei Zhan,Philip Awadalla,Philip Awadalla,Alan Hodgkinson,Yun Li,Xinghua Shi,Andrew Quitadamo,Gerton Lunter,Jonathan Marchini,Simon Myers,Claire Churchhouse,Olivier Delaneau,Olivier Delaneau,Anjali Gupta-Hinch,Warren W. Kretzschmar,Zamin Iqbal,Iain Mathieson,Androniki Menelaou,Androniki Menelaou,Andy Rimmer,Dionysia Kiara Xifara,Taras K. Oleksyk,Yunxin Fu,Xiaoming Liu,Momiao Xiong,Lynn B. Jorde,David J. Witherspoon,Jinchuan Xing,Brian L. Browning,Sharon R. Browning,Fereydoun Hormozdiari,Peter H. Sudmant,Ekta Khurana,Chris Tyler-Smith,Cornelis A. Albers,Qasim Ayub,Yuan Chen,Vincenza Colonna,Vincenza Colonna,Luke Jostins,Klaudia Walter,Yali Xue,Mark Gerstein,Alexej Abyzov,Suganthi Balasubramanian,Jieming Chen,Declan Clarke,Yao Fu,Arif Harmanci,Mike Jin,Dong-Hoon Lee,Jeremy Liu,Xinmeng Jasmine Mu,Xinmeng Jasmine Mu,Jing Zhang,Yan Zhang,Christopher Hartl,Khalid Shakir,Jeremiah D. 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Henn,Danielle Jones,Jane Kaye,Alastair Kent,Angeliki Kerasidou,Rasika A. Mathias,Pilar N. Ossorio,Michael Parker,Charles N. Rotimi,Charmaine D.M. Royal,Karla Sandoval,Yeyang Su,Zhongming Tian,Sarah A. Tishkoff,Marc Via,Yuhong Wang,Huanming Yang,Ling Yang,Jiayong Zhu,Walter F. Bodmer,Gabriel Bedoya,Zhiming Cai,Yang Gao,Jiayou Chu,Leena Peltonen,Andrés C. García-Montero,Alberto Orfao,Julie Dutil,Juan Carlos Martínez-Cruzado,R. Mathias,Anselm Hennis,Harold Watson,Colin A. McKenzie,Firdausi Qadri,Regina C. LaRocque,Xiaoyan Deng,Danny Asogun,Onikepe A. Folarin,Christian T. Happi,Omonwunmi Omoniwa,Matt Stremlau,Matt Stremlau,Ridhi Tariyal,Ridhi Tariyal,M Jallow,M Jallow,Fatoumatta Sisay Joof,Fatoumatta Sisay Joof,Tumani Corrah,Tumani Corrah,Kirk A. Rockett,Kirk A. Rockett,Dominic P. Kwiatkowski,Dominic P. Kwiatkowski,Jaspal S. Kooner,Tran Tinh Hien,Sarah J. Dunstan,Sarah J. Dunstan,Nguyen ThuyHang,Richard Fonnie,Robert F. Garry,Lansana Kanneh,Lina M. Moses,John S. Schieffelin,Donald S. Grant,Carla Gallo,Giovanni Poletti,Danish Saleheen,Asif Rasheed,Lisa D. Brooks,Adam Felsenfeld,Jean E. McEwen,Yekaterina Vaydylevich,Audrey Duncanson,Michael Dunn,Jeffery A. Schloss +517 more