Nat Genet. 2009 Dec;41(12):1313-8. doi: 10.1038/ng.479. Epub 2009 Nov 8.
Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk.
Raychaudhuri S,
Thomson BP,
Remmers EF,
Eyre S,
Hinks A,
Guiducci C,
Catanese JJ,
Xie G,
Stahl EA,
Chen R,
Alfredsson L,
Amos CI,
Ardlie KG;
BIRAC Consortium,
Barton A,
Bowes J,
Burtt NP,
Chang M,
Coblyn J,
Costenbader KH,
Criswell LA,
Crusius JB,
Cui J,
De Jager PL,
Ding B,
Emery P,
Flynn E,
Harrison P,
Hocking LJ,
Huizinga TW,
Kastner DL,
Ke X,
Kurreeman FA,
Lee AT,
Liu X,
Li Y,
Martin P,
Morgan AW,
Padyukov L,
Reid DM,
Seielstad M,
Seldin MF,
Shadick NA,
Steer S,
Tak PP,
Thomson W,
van der Helm-van Mil AH,
van der Horst-Bruinsma IE,
Weinblatt ME,
Wilson AG,
Wolbink GJ,
Wordsworth P;
YEAR Consortium,
Altshuler D,
Karlson EW,
Toes RE,
de Vries N,
Begovich AB,
Siminovitch KA,
Worthington J,
Klareskog L,
Gregersen PK,
Daly MJ,
Plenge RM.
Bruce IN, Hyrich K, Ho P, Gorodkin R, Badcock LJ, Deighton CM, O'Reilly SC, Raj N, Regan MR, Summers GD, Williams RA, Barton A, Knight SM, Symmons DP, Sanders P, Pal B, Gaffney K, Macgregor AJ, Marshall T, Merry P, Scott DG, Porter D, Madok R, Gordon M, McInnes I, Sturrock R, Field M, Harrison B, Pattrick M, Snowden HN, Bowden AP, Smith EE, Klimiuk P, Speden DJ, Thompson PW, Richards SC, Hull RG, Ledingham JM, Mccrae F, Shaban MR, Thomas AL, Young Min SA, Herrick AL, Cooper RG, Benitha R, Jones AK, O'Neill TW, Abernethy VE, Clewes AR, Dawson JK, Lynch M, Kitas G, Delamere JP, Erb N, Klocke R, Whallett AJ, Dawes PT, Dowson CM, Hassell A, Hay EM, Kamath S, Packham J, Sandhu RS, Shadforth MF, Bingham S, Emery P, Morgan A, Bird HA, Conaghan PG, Pease CT, Wakefield RJ, Chalam SV, Mulherin D, Price T, Sheeran T, Venkatachalam S, Crook P, Foster HE, Griffiths B, Griffiths ID, Grove ML, Isaacs JD, Kay L, Ng WF, Myers A, Platt PN, Walker DJ, Lim KL, Walsh DA, Carter ND, Holt M, Fawthrop FW, Smith GW, Emery P, Conaghan P, Morgan A, Quinn M, Keenan AM, Hensor E, Gough A, Green M, Reece R, Hordon L, Helliwell P, Melsom R, Doherty S, Adebajo A, Harvey A, Jarrett S, Huson G, Isdale A, Martin M, Karim Z, McGonagle D, Pease C, Cox S, Bejarano V, Nam J, Brown C, Thomas C, Pickles D, Hammond A, Neville B, Fairclough A, Nunns C, Gill A, Green J, Rhys-Evans B, Padwell B, Madden J, Taylor L, Smith S, King H, Firth J, Heard J, Sigsworth L, Corscadden D, Henshaw K, Rashid LH, Martin SG, Robinson JI.
Source
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. soumya@broad.mit.edu
Abstract
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. We used Gene Relationships Across Implicated Loci (GRAIL), 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. 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.
- PMID:
- 19898481
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3142887
Free PMC ArticleFigure 1Using Gene Relationships Across Implicated Loci (GRAIL) to prioritize candidate RA SNPs
We select a set of candidate SNPs to pursue in an independent genotyping experiment by starting with all SNPs that obtain p<0.001 in an independent GWAS meta-analysis. Then for each candidate SNP, GRAIL identifies the genomic region in LD, and identifies overlapping genes. It then checks to see how many other loci, already known to be associated with disease, contain functionally related genes. SNPs representing those candidate loci with significantly related genes are forwarded for genotyping in large numbers of independent case-control samples.
Nat Genet. 2009 December;41(12):1313-1318.
Figure 3
A. GRAIL identifies 22 SNPs among the 179 candidate SNPs with p<0.001 in a GWAS meta-analysis. We plot a histogram of the 179 SNPs as a function of their GWAS meta-analysis p-value. Gray bars represent the 157 SNPs that were not selected, while colored bars represent the 22 SNPs that were selected; purple indicating SNPs that replicated convincingly in follow-up genotyping (p<0.0023), orange indicating nominally associated SNPs in follow-up genotyping (p<0.05), and yellow indicating genotyped SNPs without any independent evidence of association. 3B. Enrichment of SNPs with z-scores >2 in replication samples. For each of the 22 SNPs tested, we calculated a one-sided CMH z-score statistic from our two-staged replication data. A z-score of 0 corresponds to a p=0.5; a z-score of 1.65 corresponds to a p=0.05; and a z-score of 2.83 corresponds to p=0.0023. For a random collection of unassociated SNPs, this histogram should approximate a normal distribution (dotted line).
Nat Genet. 2009 December;41(12):1313-1318.
Figure 2GRAIL identifies inter-connectivity among genes in RA loci
We place the known RA associated SNP along the outer ring; the internal ring represents the genes near each SNP (as listed in Table 1) with a box. We illustrate the literature-based functional connectivity between these genes with lines drawn between them - the redder and thicker the lines are the stronger the connectivity between the genes is. RA SNPs implicate a small number of highly connected genes – those genes are indicated by labeled boxes.
Nat Genet. 2009 December;41(12):1313-1318.
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