Journal
NATURE GENETICS
Volume 44, Issue 12, Pages 1336-1340Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2462
Keywords
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Categories
Funding
- Arthritis Research UK [17552]
- Manchester Biomedical Research Centre
- Arthritis Foundation
- Uppsala University
- Uppsala University Hospital
- Science for Life Laboratory-Uppsala
- Swedish Research Council [80576801, 70374401]
- Redes Tematicas de Investigacion Cooperative en Salud (RETICS) Program, Instituto de Salud Carlos III, Spain [RD08/0075]
- Wellcome Trust [076113/C/04/Z, 068545/Z/02]
- US National Institutes for Health research program [RP-PG-0310-1002]
- UK Medical Research Council [G0000934]
- US National Institutes of Health [K08AR055688, 1R01AR062886-01, RO1-AR-4-4422, NO1-AR-2-2263, NO1-AR1-2256, RO1 AI068759, RC2AR059092-01, R01-AR057108, R01-AR056768, U01-GM092691, R01-AR059648]
- Eileen Ludwig Greenland Center for Rheumatoid Arthritis
- family of Robert S. Boas
- Burroughs Wellcome Fund
- MRC [MC_U147585819, G0800759, G0000934, G0400491, G0600329, G0800675, MC_U147585827] Funding Source: UKRI
- Cancer Research UK
- Versus Arthritis [18475] Funding Source: researchfish
- Chief Scientist Office [ETM/75, ETM/137, CZB/4/540] Funding Source: researchfish
- Medical Research Council [MC_U147585819, G0800759, G0800675, G0600329, U1475000001, G0400491, MC_U147585824, G0000934, MC_U147585827, MC_UP_A620_1014] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10219, NF-SI-0508-10082, NF-SI-0508-10335, NF-SI-0508-10299] Funding Source: researchfish
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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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