High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis by Eyre Steve, Bowes John, Diogo Dorothée, Lee Annette, Barton Anne, Martin Paul, Zhernakova Alexandra, Stahl Eli, Viatte Sebastien, McAllister Kate, Amos Christopher I, Padyukov Leonid, Toes Rene E M, Huizinga Tom W J, Wijmenga Cisca, Trynka Gosia, Franke Lude, Westra Harm-Jan, 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, Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate, Wellcome Trust Case Control Consortium, Concannon Pat, Onengut-Gumuscu Suna, Rich Stephen S, Deloukas Panos, Gonzalez-Gay Miguel A, Rodriguez-Rodriguez Luis, Arlsetig Lisbeth, Martin Javier, Rantapää-Dahlqvist Solbritt, Plenge Robert M, Raychaudhuri Soumya, Klareskog Lars, Gregersen Peter K, Worthington Jane in Nature genetics (2012).

[PMID: 23143596] PubMed


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.

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