1. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis
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Mark Caulfield, Solbritt Rantapää Dahlqvist, Eleftheria Zeggini, Michael Weedon, Paul Martin, Elaine Dennison, Patricia Munroe, Detelina Grozeva, John Isaacs, Stephen Eyre, Alex MacGregor, Kate Duffus, Andrew Hattersley, DOROTHEE DIOGO, Luis Rodriguez-Rodriguez, Steven Young-Min, Chris Wallace, Miguel Gonzalez-Gay, Tom Huizinga, Stephen Newhouse, Alexandra Zhernakova, Melanie Newport, Deborah Symmons, Lisa Jones, Michael O'Donovan, Wan-Fai Ng, Nadira Yusupovna Yuldasheva, Cyrus Cooper, Willem Ouwehand, Philip Conaghan, Gerome Breen, Lars Alfredsson, Karim Raza, Hana Lango Allen, Jane Worthington, Mark Iles, Ann Morgan, Professor David Dunger, Soumya Raychaudhuri, Panos Deloukas, Marwan Bukhari, Alastair Forbes, Allan Young, Lars Klareskog, Leonid Padyukov, Fraser Birrell, Charlie Lees, Anne Barton, Martin Tobin, Patrick Concannon, Jon Packham, Natalie Prescott, Javier Martin, Kimme Hyrich, Lude Franke, John Bowes, Ian Bruce, Chiea Chuen Khor, Stephen Rich, Miles Parkes, Sarah Hunt, Tim Bishop, Gosia Trynka, Richard Dobson, Anna Dominiczak, Cisca Wijmenga, Mark McCarthy, Cecilia Lindgren, Rene Toes, Alistair Hall, Faculteit Medische Wetenschappen/UMCG, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Bowes, John [0000-0003-4659-031X], Zhernakova, Alexandra [0000-0002-4574-0841], Padyukov, Leonid [0000-0003-2950-5670], Toes, Rene EM [0000-0002-9618-6414], Wijmenga, Cisca [0000-0002-5635-1614], Trynka, Gosia [0000-0002-6955-9529], Franke, Lude [0000-0002-5159-8802], Alfredsson, Lars [0000-0003-1688-6697], Khor, Chiea Chuen [0000-0002-1128-4729], Concannon, Pat [0000-0002-5801-1859], Onengut-Gumuscu, Suna [0000-0002-6563-8334], Rodriguez-Rodriguez, Luis [0000-0002-2869-7861], Rantapää-Dahlqvist, Solbritt [0000-0001-8259-3863], Raychaudhuri, Soumya [0000-0002-1901-8265], Klareskog, Lars [0000-0001-9601-6186], and Apollo - University of Cambridge Repository
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EXPRESSION ,Male ,Arthritis ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,White People ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Gene mapping ,Polymorphism (computer science) ,Genetics ,medicine ,SNP ,Humans ,CORONARY-HEART-DISEASE ,Genetic Predisposition to Disease ,Genotyping ,METAANALYSIS ,030304 developmental biology ,Genetic association ,Autoantibodies ,Oligonucleotide Array Sequence Analysis ,030203 arthritis & rheumatology ,0303 health sciences ,Chromosome Mapping ,ASSOCIATION ,medicine.disease ,RISK LOCI ,INTERLEUKIN-6 RECEPTOR ,Genetic Loci ,Female ,SNP array ,Genome-Wide Association Study - 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.
- Published
- 2021
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