期刊
NATURE GENETICS
卷 41, 期 12, 页码 1313-U76出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.479
关键词
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资金
- US National Institutes of Health (NIH) Career Development Award [1K08AR055688-01A1]
- American College of Rheumatology Bridge Grant
- NIH [AI55314-3, U01 HG004171, DK62432, R01 DK083756-1, DK64869, NO1-AR-2-2263, RO1 AR44422]
- Fox Trot Fund
- William Randolph Hearst Fund of Harvard University
- Burroughs Wellcome Fund
- National Center for Research Resources [U54 RR020278]
- Millennium Pharmaceuticals
- Intramural Research Program of the National Institute of Arthritis
- Musculoskeletal and Skin Diseases of the NIH
- Canadian Institutes for Health Research [MOP79321, IIN-84042]
- Ontario Research Fund [RE01061]
- Canada Research Chair
- Biogen-Idec
- National Heart, Lung, and Blood Institute's (STAMPEED)
- [R01HL087676]
- National Institute for Health Research [NF-SI-0508-10299] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [18475] Funding Source: researchfish
To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls(1). We used Gene Relationships Across Implicated Loci (GRAIL)(2), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci(1,3-11). We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 x 10(-6) replication, P = 1 x 10(-9) overall), CD28 (rs1980422, P = 5 x 10(-6) replication, P = 1 x 10(-9) overall) and PRDM1 (rs548234, P = 1 x 10(-5) replication, P = 2 x 10(-8) overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 x 10(-7) overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 x 10(-7) overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 x 10(-6) overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 x 10(-5) overall). Many of these loci are also associated to other immunologic diseases.
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