Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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

Soumya Raychaudhuri  1 , Brian P Thomson, Elaine F Remmers, Stephen Eyre, Anne Hinks, Candace Guiducci, Joseph J Catanese, Gang Xie, Eli A Stahl, Robert Chen, Lars Alfredsson, Christopher I Amos, Kristin G Ardlie; BIRAC Consortium; Anne Barton, John Bowes, Noel P Burtt, Monica Chang, Jonathan Coblyn, Karen H Costenbader, Lindsey A Criswell, J Bart A Crusius, Jing Cui, Phillip L De Jager, Bo Ding, Paul Emery, Edward Flynn, Pille Harrison, Lynne J Hocking, Tom W J Huizinga, Daniel L Kastner, Xiayi Ke, Fina A S Kurreeman, Annette T Lee, Xiangdong Liu, Yonghong Li, Paul Martin, Ann W Morgan, Leonid Padyukov, David M Reid, Mark Seielstad, Michael F Seldin, Nancy A Shadick, Sophia Steer, Paul P Tak, Wendy Thomson, Annette H M van der Helm-van Mil, Irene E van der Horst-Bruinsma, Michael E Weinblatt, Anthony G Wilson, Gert Jan Wolbink, Paul Wordsworth; YEAR Consortium; David Altshuler, Elizabeth W Karlson, Rene E M Toes, Niek de Vries, Ann B Begovich, Katherine A Siminovitch, Jane Worthington, Lars Klareskog, Peter K Gregersen, Mark J Daly, Robert M Plenge
Collaborators, Affiliations

Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk

Soumya Raychaudhuri et al. Nat Genet. 2009 Dec.

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Using 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.
Figure 2
Figure 2. GRAIL 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.
Figure 3
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).
Figure 3
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).
See this image and copyright information in PMC

References

    1. Raychaudhuri S, et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet. 2008;40:1216–23. - PMC - PubMed
    1. Raychaudhuri S, et al. Identifying Relationships Among Genomic Disease Regions: Predicting Genes at Pathogenic SNP Associations and Rare Deletions. PLOS Genetics. 2009;5:e1000534. - PMC - PubMed
    1. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30:1205–13. - PubMed
    1. Begovich AB, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004;75:330–7. - PMC - PubMed
    1. Plenge RM, et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet. 2007;39:1477–1482. - PMC - PubMed

Publication types