High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Steve Eyre; John Bowes; Dorothée Diogo; Annette Lee; Anne Barton; Paul Martin; Alexandra Zhernakova; Eli Stahl; Sebastien Viatte; Kate McAllister; Christopher I Amos; Leonid Padyukov; Rene E M Toes; Tom W J Huizinga; Cisca Wijmenga; Gosia Trynka; Lude Franke; Harm-Jan Westra; 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; Pat Concannon; Suna Onengut-Gumuscu; Stephen S Rich; Panos Deloukas; Miguel A Gonzalez-Gay; Luis Rodriguez-Rodriguez; Lisbeth Ärlsetig; Javier Martin; Solbritt Rantapää-Dahlqvist; Robert M Plenge; Soumya Raychaudhuri; Lars Klareskog; Peter K Gregersen; Jane Worthington; Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate; Alastair Forbes

doi:10.1038/ng.2462

High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Steve Eyre, John Bowes, Dorothée Diogo, Annette Lee, Anne Barton, Paul Martin, Alexandra Zhernakova, Eli Stahl, Sebastien Viatte, Kate McAllister, Christopher I Amos, Leonid Padyukov, Rene E M Toes, Tom W J Huizinga, Cisca Wijmenga, Gosia Trynka, Lude Franke, Harm-Jan Westra, Lars Alfredsson, Xinli HuCynthia 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, Pat Concannon, Suna Onengut-Gumuscu, Stephen S Rich, Panos Deloukas, Miguel A Gonzalez-Gay, Luis Rodriguez-Rodriguez, Lisbeth Ärlsetig, Javier Martin, Solbritt Rantapää-Dahlqvist, Robert M Plenge, Soumya Raychaudhuri, Lars Klareskog, Peter K Gregersen, Jane Worthington, Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate, Alastair Forbes

Research output: Contribution to journal › Article › peer-review

518 Citations (SciVal)

Abstract

Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

Original language	English
Pages (from-to)	1336-40
Number of pages	5
Journal	Nature Genetics
Volume	44
Issue number	12
DOIs	https://doi.org/10.1038/ng.2462
Publication status	Published - Dec 2012

Keywords

Arthritis, Rheumatoid
Autoantibodies
Chromosome Mapping
European Continental Ancestry Group
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide

Access to Document

10.1038/ng.2462

Cite this

Eyre, S., Bowes, J., Diogo, D., Lee, A., Barton, A., Martin, P., Zhernakova, A., Stahl, E., Viatte, S., McAllister, K., Amos, C. I., Padyukov, L., Toes, R. E. M., Huizinga, T. W. J., Wijmenga, C., Trynka, G., Franke, L., Westra, H-J., Alfredsson, L., ... Forbes, A. (2012). High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nature Genetics, 44(12), 1336-40. https://doi.org/10.1038/ng.2462

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title = "High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis",

abstract = "Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.",

keywords = "Arthritis, Rheumatoid, Autoantibodies, Chromosome Mapping, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide",

author = "Steve Eyre and John Bowes and Doroth{\'e}e Diogo and Annette Lee and Anne Barton and Paul Martin and Alexandra Zhernakova and Eli Stahl and Sebastien Viatte and Kate McAllister and Amos, {Christopher I} and Leonid Padyukov and Toes, {Rene E M} and Huizinga, {Tom W J} and Cisca Wijmenga and Gosia Trynka and Lude Franke and Harm-Jan Westra 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 Pat Concannon and Suna Onengut-Gumuscu and Rich, {Stephen S} and Panos Deloukas and Gonzalez-Gay, {Miguel A} and Luis Rodriguez-Rodriguez and Lisbeth {\"A}rlsetig and Javier Martin and Solbritt Rantap{\"a}{\"a}-Dahlqvist and Plenge, {Robert M} and Soumya Raychaudhuri and Lars Klareskog and Gregersen, {Peter K} and Jane Worthington and {Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate} and Alastair Forbes",

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month = dec,

doi = "10.1038/ng.2462",

language = "English",

volume = "44",

pages = "1336--40",

journal = "Nature Genetics",

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Eyre, S, Bowes, J, Diogo, D, Lee, A, Barton, A, Martin, P, Zhernakova, A, Stahl, E, Viatte, S, McAllister, K, Amos, CI, Padyukov, L, Toes, REM, Huizinga, TWJ, Wijmenga, C, Trynka, G, Franke, L, Westra, H-J, 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, SS, Deloukas, P, Gonzalez-Gay, MA, Rodriguez-Rodriguez, L, Ärlsetig, L, Martin, J, Rantapää-Dahlqvist, S, Plenge, RM, Raychaudhuri, S, Klareskog, L, Gregersen, PK, Worthington, J, Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate & Forbes, A 2012, 'High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis', Nature Genetics, vol. 44, no. 12, pp. 1336-40. https://doi.org/10.1038/ng.2462

TY - JOUR

T1 - High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

AU - Eyre, Steve

AU - Bowes, John

AU - Diogo, Dorothée

AU - Lee, Annette

AU - Barton, Anne

AU - Martin, Paul

AU - Zhernakova, Alexandra

AU - Stahl, Eli

AU - Viatte, Sebastien

AU - McAllister, Kate

AU - Amos, Christopher I

AU - Padyukov, Leonid

AU - Toes, Rene E M

AU - Huizinga, Tom W J

AU - Wijmenga, Cisca

AU - Trynka, Gosia

AU - Franke, Lude

AU - Westra, Harm-Jan

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, Pat

AU - Onengut-Gumuscu, Suna

AU - Rich, Stephen S

AU - Deloukas, Panos

AU - Gonzalez-Gay, Miguel A

AU - Rodriguez-Rodriguez, Luis

AU - Ärlsetig, Lisbeth

AU - Martin, Javier

AU - Rantapää-Dahlqvist, Solbritt

AU - Plenge, Robert M

AU - Raychaudhuri, Soumya

AU - Klareskog, Lars

AU - Gregersen, Peter K

AU - Worthington, Jane

AU - Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate

AU - Forbes, Alastair

PY - 2012/12

Y1 - 2012/12

N2 - Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

AB - Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

KW - Arthritis, Rheumatoid

KW - Autoantibodies

KW - Chromosome Mapping

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Oligonucleotide Array Sequence Analysis

KW - Polymorphism, Single Nucleotide

U2 - 10.1038/ng.2462

DO - 10.1038/ng.2462

M3 - Article

C2 - 23143596

VL - 44

SP - 1336

EP - 1340

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 12

ER -