High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Polymorphisms in the IL6RA gene are associated with susceptibility to both RA and IBD.
“An association between polymorphisms in the IL6RA gene and susceptibility to both RA and IBD have been found (77, 78).”
From T <sub>H</sub> 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity (2020) · cites this paper as [77]
The passage labeled Abstract (page not supplied) identifies IL6R as a rheumatoid arthritis susceptibility locus and reports an association for an IL6R-linked SNP. It does not report an association between IL6R polymorphisms and IBD susceptibility; searches for IBD, Crohn disease, and ulcerative colitis did not find one. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe IL6RA variant rs2228145 is associated with reduced risk of both RA and IBD.
“is associated with reduced risk of both RA (77) and IBD (78).”
From T <sub>H</sub> 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity (2020) · cites this paper as [77]
The IL6R discussion (page unavailable) reports an association with rheumatoid arthritis and says an IL6R-linked allele is protective (OR=0.9). This citation is attached to the RA portion of the sentence, not the IBD portion. Our copy names rs8192284 and the linked rs4129267, but does not identify either as rs2228145, so it does not establish the claim for that specific variant. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
(2012) · The Lancet · doi:10.1016/s0140-6736(12)60110-x · Cited by 1,146 · see citing works
(2012) · The Lancet · doi:10.1016/s0140-6736(11)61931-4 · Cited by 823 · see citing works
Practical aspects of imputation-driven meta-analysis of genome-wide association studies
de Bakker, P. I. W., Ferreira, M. A. R., Jia, X., Neale, B. M., Raychaudhuri, S., & Voight, B. F. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn288 · Cited by 531 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 18
- [1]Stahl EA Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci Nat. Genet 2010 42 508 514 20453842 PMC4243840
- [2]Zhernakova A Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci PLoS. Genet 2011 7 e1002004 21383967 PMC3044685
- [3]Trynka G Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease Nat. Genet 2011 43 1193 1201 22057235 PMC3242065
- [4]Stahl EA Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis Nat. Genet 2012 22446960 PMC6560362
- [5]Raychaudhuri S Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis Nat. Genet 2012 44 291 296 22286218 PMC3288335
- [6]Padyukov L A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis Ann. Rheum. Dis 2011 70 259 265 21156761 PMC3015094
- [7]Jacob CO Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus Proc. Natl. Acad. Sci. U. S. A 2009 106 6256 6261 19329491 PMC2669395
- [8]Carrel L Willard HF X-inactivation profile reveals extensive variability in X-linked gene expression in females Nature 2005 434 400 404 15772666
- [9]Suzuki A Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis Nat. Genet 2003 34 395 402 12833157
- [10]Kurreeman FA Use of a Multiethnic Approach to Identify Rheumatoid-Arthritis-Susceptibility Loci, 1p36 and 17q12 Am. J. Hum. Genet 2012 90 524 532 22365150 PMC3309197
- [11]Okada Y Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population Nat. Genet 2012 22446963
- [14]Ferreira MA Identification of IL6R and chromosome 11q13.5 as risk loci for asthma Lancet 2011 378 1006 1014 21907864 PMC3517659
- [15]Stevens L Involvement of GATA3 in protein kinase C theta-induced Th2 cytokine expression Eur. J. Immunol 2006 36 3305 3314 17111354
- [16]Hu X Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets Am. J. Hum. Genet 2011 89 496 506 21963258 PMC3188838
- [17]Heng TS Painter MW The Immunological Genome Project: networks of gene expression in immune cells Nat. Immunol 2008 9 1091 1094 18800157
- [18]Delaneau O Marchini J Zagury JF A linear complexity phasing method for thousands of genomes Nat. Methods 2012 9 179 181 22138821
- [19]Marchini J Howie B Myers S McVean G Donnelly P A new multipoint method for genome-wide association studies by imputation of genotypes Nat. Genet 2007 39 906 913 17572673
- [22]Fehrmann RS Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA PLoS. Genet 2011 7 e1002197 21829388 PMC3150446
Cited by
Sorted by citations
Visscher, P. M., Brown, M. A., McCarthy, M. I., & Yang, J. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.11.029 · Cited by 2,425 · see citing works
Genetic and epigenetic fine mapping of causal autoimmune disease variants
Farh, K. K.-H., Marson, A., Zhu, J., Kleinewietfeld, M., Housley, W. J., Beik, S., Shoresh, N., Whitton, H., Ryan, R. J. H., Shishkin, A. A., et al. (2015) · Nature · doi:10.1038/nature13835 · Cited by 1,956 · see citing works
Complex genetic signatures in immune cells underlie autoimmunity and inform therapy
Orrù, V., Steri, M., Sidore, C., Marongiu, M., Serra, V., Olla, S., Sole, G., Lai, S., Dei, M., Mulas, A., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0684-4 · Cited by 1,246 · see citing works
Validating therapeutic targets through human genetics
Plenge, R. M., Scolnick, E. M., & Altshuler, D. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4051 · Cited by 712 · see citing works
Self-citationChromatin marks identify critical cell types for fine mapping complex trait variants
Trynka, G., Sandor, C., Han, B., Xu, H., Stranger, B. E., Liu, X. S., & Raychaudhuri, S. (2013) · Nature Genetics · doi:10.1038/ng.2504 · Cited by 580 · see citing works
Self-citationMethodological Challenges in Mendelian Randomization
VanderWeele, T. J., Tchetgen Tchetgen, E. J., Cornelis, M., & Kraft, P. (2014) · Epidemiology · doi:10.1097/ede.0000000000000081 · Cited by 555 · see citing works
Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank
Szustakowski, J. D., Balasubramanian, S., Kvikstad, E., Khalid, S., Bronson, P. G., Sasson, A., Wong, E., Liu, D., Wade Davis, J., Haefliger, C., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00885-0 · Cited by 401 · see citing works
Self-citationFerreira, R. C., Freitag, D. F., Cutler, A. J., Howson, J. M. M., Rainbow, D. B., Smyth, D. J., Kaptoge, S., Clarke, P., Boreham, C., Coulson, R. M., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003444 · Cited by 316 · see citing works
Self-citationRoederer, M., Quaye, L., Mangino, M., Beddall, M. H., Mahnke, Y., Chattopadhyay, P., Tosi, I., Napolitano, L., Terranova Barberio, M., Menni, C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.02.046 · Cited by 296 · see citing works
Harbour, S. N., DiToro, D. F., Witte, S. J., Zindl, C. L., Gao, M., Schoeb, T. R., Jones, G. W., Jones, S. A., Hatton, R. D., & Weaver, C. T. (2020) · Science Immunology · doi:10.1126/sciimmunol.aaw2262 · Cited by 151 · see citing works
Karnes, J. H., Bastarache, L., Shaffer, C. M., Gaudieri, S., Xu, Y., Glazer, A. M., Mosley, J. D., Zhao, S., Raychaudhuri, S., Mallal, S., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aai8708 · Cited by 126 · see citing works
Self-citationZhu, M., Xu, K., Chen, Y., Gu, Y., Zhang, M., Luo, F., Liu, Y., Gu, W., Hu, J., Xu, H., et al. (2019) · Diabetes Care · doi:10.2337/dc18-2023 · Cited by 100 · see citing works
Sensitive detection of chromatin-altering polymorphisms reveals autoimmune disease mechanisms
del Rosario, R. C.-H., Poschmann, J., Rouam, S. L., Png, E., Khor, C. C., Hibberd, M. L., & Prabhakar, S. (2015) · Nature Methods · doi:10.1038/nmeth.3326 · Cited by 58 · see citing works
Self-citationHu, X., Kim, H., Raj, T., Brennan, P. J., Trynka, G., Teslovich, N., Slowikowski, K., Chen, W.-M., Onengut, S., Baecher-Allan, C., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004404 · Cited by 52 · see citing works
Self-citationFrom Identification to Characterization of the Multiple Sclerosis Susceptibility Gene CLEC16A
Berge, T., Leikfoss, I., & Harbo, H. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14034476 · Cited by 45 · see citing works
Hoefsmit, E. P., Rozeman, E. A., Haanen, J. B. A. G., & Blank, C. U. (2019) · ESMO Open · doi:10.1136/esmoopen-2018-000472 · Cited by 29 · see citing works
Ferreira, R. C., Rainbow, D. B., Rubio García, A., Pekalski, M. L., Porter, L., Oliveira, J. J., Waldron-Lynch, F., Wicker, L. S., & Todd, J. A. (2017) · Clinical Immunology · doi:10.1016/j.clim.2017.03.002 · Cited by 19 · see citing works
- Authors
- Syndicate, B. I. R. A. G. A. G. S., Eyre, S., Wellcome Trust Case Control Consortium, 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., Hu, X., Sandor, C., de Bakker, P. I. W., Davila, S., Khor, C. C., Heng, K. K., Andrews, R., Edkins, S., Hunt, S. E., Langford, C., Symmons, D., Concannon, P., Onengut-Gumuscu, S., Rich, S. S., Deloukas, P., Gonzalez-Gay, M. A., Rodriguez-Rodriguez, L., Ärlsetig, L., Martin, J., Rantapää-Dahlqvist, S., Plenge, R. M., Raychaudhuri, S., Klareskog, L., Gregersen, P. K., & Worthington, J.
- Affiliations
- National Health Service (GB)
- Broad Institute (US)
- Karolinska University Hospital (SE)
- University Medical Center Groningen (NL)
- Genome Institute of Singapore (SG)
- Wellcome Sanger Institute (GB)
- Consejo Superior de Investigaciones Científicas (ES)
- Northwell Health (US)
- Corresponding author
- Worthington, Jane
- ORCID
- Bowes, John
- Diogo, Dorothée
- Lee, Annette
- Barton, Anne
- Martin, Paul
- Zhernakova, Alexandra
- Stahl, Eli
- Padyukov, Leonid
- Huizinga, Tom W J
- Wijmenga, Cisca
- Trynka, Gosia
- Franke, Lude
- Westra, Harm-Jan
- Alfredsson, Lars
- Hu, Xinli
- Sandor, Cynthia
- Khor, Chiea Chuen
- Edkins, Sarah
- Hunt, Sarah E
- Langford, Cordelia
- Symmons, Deborah
- Rich, Stephen S
- Deloukas, Panos
- Martin, Javier
- Plenge, Robert M
- Raychaudhuri, Soumya
- Klareskog, Lars
- Gregersen, Peter K
- Worthington, Jane
- Venue
- Nature Genetics
- Published
- 2012-11-11
- Volume
- 44
- Issue
- 12
- Pages
- 1336-1340
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3605761
- OpenAlex
- W2132576596
- Cited by
- 653
- References
- 4
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 43 · 2023: 31 · 2022: 59 · 2021: 49 · 2020: 39 · 2019: 49 · 2018: 38 · 2017: 34 · 2016: 54 · 2015: 78 · 2014: 76 · 2013: 60 · 2012: 4
- FWCI
- 53.63
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open Research Exeter (University of Exeter) (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Apollo
- Funders
- NHS Blood and Transplant
- Wellcome Trust (068545/Z/02), 091157, G0000934, 17552, 068545, 091157/Z/10/Z, 090532, 076113, 076113/C/04/Z, 091157/Z/10/B)
- National Institute for Health and Care Research (RP-PG-0310-1002, NF-SI-0508-10299, NF-SI-0508-10082, NF-SI-0611-10219, NF-SI-0508-10335)
- Vetenskapsrådet (70374401, 80576801)
- Akademiska Sjukhuset
- Uppsala Universitet
- Science for Life Laboratory
- Versus Arthritis (/17552, 18475)
- National Institutes of Health (G0000934, NO1-AR-2–2263, 068545/Z/02)
- Manchester Biomedical Research Centre
- Medical Research Council (068545/Z/02, G0000934)
- Instituto de Salud Carlos III (RD08/0075)
- National Institute of General Medical Sciences (U01GM092691)
- National Institute of Allergy and Infectious Diseases (R01AI068759)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (N01-AR-22263, N01-AR1-2256, R01 AR44422, R01AR062886, RC2AR059092, K08AR055688, R01AR059648, R01AR056768, R01AR057108)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- rheumatoid arthritis, genetic susceptibility loci, high-density genotyping, single nucleotide polymorphisms, anti-citrullinated protein antibodies, European ancestry, low-frequency variants, immunochip
- MeSH terms
- Arthritis, Rheumatoid, Autoantibodies, Chromosome Mapping, Female, Humans, Male, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study, Genetic Loci
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
