Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23

Orozco, G., Hinks, A., Eyre, S., Ke, X., Gibbons, L. J., Bowes, J., Flynn, E., Martin, P., Wilson, A. G., Bax, D. E., Morgan, A. W., Emery, P., Steer, S., Hocking, L., Reid, D. M., Wordsworth, P., Harrison, P., Thomson, W., Barton, A., Worthington, J., Fraser, Christine, Green, Elaine, Grozeva, Detelina, Hamshere, Marian Lindsay ORCID: https://orcid.org/0000-0002-8990-0958, Holmans, Peter Alan ORCID: https://orcid.org/0000-0003-0870-9412, Jones, Ian Richard ORCID: https://orcid.org/0000-0001-5821-5889, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Nikolov, Ivan, O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379, Owen, Michael John ORCID: https://orcid.org/0000-0003-4798-0862 and Craddock, Nicholas John ORCID: https://orcid.org/0000-0003-2171-0610 2009. Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23. Human Molecular Genetics 18 (14) , pp. 2693-2699. 10.1093/hmg/ddp193

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Abstract

The most consistent finding derived from the WTCCC GWAS for rheumatoid arthritis (RA) was association to a SNP at 6q23. We performed a fine-mapping of the region in order to search the 6q23 region for additional disease variants. 3962 RA patients and 3531 healthy controls were included in the study. We found 18 SNPs associated with RA. The SNP showing the strongest association was rs6920220 [P = 2.6 x 10(-6), OR (95% CI) 1.22 (1.13-1.33)]. The next most strongly associated SNP was rs13207033 [P = 0.0001, OR (95% CI) 0.86 (0.8-0.93)] which was perfectly correlated with rs10499194, a SNP previously associated with RA in a US/European series. Additionally, we found a number of new potential RA markers, including rs5029937, located in the intron 2 of TNFAIP3. Of the 18 associated SNPs, three polymorphisms, rs6920220, rs13207033 and rs5029937, remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of rs6920220 and rs5029937 together with the absence of the protective allele of rs13207033 was strongly associated with RA when compared with carriage of none [OR of 1.86 (95% CI) (1.51-2.29)]. This equates to an effect size of 1.50 (95% CI 1.21-1.85) compared with controls and is higher than that obtained for any SNP individually. This is the first study to show that the confirmed loci from the GWA studies, that confer only a modest effect size, could harbour a significantly greater effect once the effect of additional risk variants are accounted for.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	R Medicine > R Medicine (General)
Additional Information:	Christine Fraser, Elaine Green, Detelina Grozeva, Marian Hamshere, Peter Holmans, Ian Jones, George Kirov, Valentina Escott-Price (nee Moskvina), Ivan Nikolov, Michael O'Donovan, Michael Owen and Nick Craddock are collaborators on this article.
Publisher:	Oxford University Press
ISSN:	0964-6906
Last Modified:	17 Nov 2022 12:04
URI:	https://orca.cardiff.ac.uk/id/eprint/81523

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