Abstract
In a recent genome-wide association study (GWAS) based on 12 374 non-synonymous single nucleotide polymorphisms we identified a number of candidate multiple sclerosis susceptibility genes. Here, we describe the extended analysis of 17 of these loci undertaken using an additional 4234 patients, 2983 controls and 2053 trio families. In the final analysis combining all available data, we found that evidence for association was substantially increased for one of the 17 loci, rs34536443 from the tyrosine kinase 2 (TYK2) gene (P=2.7 × 10−6, odds ratio=1.32 (1.17–1.47)). This single nucleotide polymorphism results in an amino acid substitution (proline to alanine) in the kinase domain of TYK2, which is predicted to influence the levels of phosphorylation and therefore activity of the protein and so is likely to have a functional role in multiple sclerosis.
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Acknowledgements
We thank members of the Association of British Neurologists for notifying families. We acknowledge contributions from the International Multiple Sclerosis Genetics Consortium. This work was supported by the Medical Research Council (G0700061) and the National Institute of Health (NS 049477-01A1). We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. The Norwegian Bone Marrow Donor Registry is acknowledged for collaboration in the establishment of the Norwegian control material. AG is a Postdoctoral Fellow, EB a Research Assistant, and BD a Clinical Investigator of the Research Foundation Flanders (FWO-Vlaanderen). ARL and HFH are supported by The Research Council of Norway (166005/V5), the Ullevål University Hospital Scientific Advisory Council and by the Odd Fellow MS society. This study makes use of data generated by The Wellcome Trust Case–Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by The Wellcome Trust under award 076113 and reported in Nature 2007; 447; 661–78.
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StatsDirect statistical software – http://www.statsdirect.com.
PolyPhen – http://genetics.bwh.harvard.edu/pph/.
SIFT – http://blocks.fhcrc.org/sift/SIFT.html.
Supplementary information accompanies the paper on European Journal of Human Genetics website (http://www.nature.com/ejhg)
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Ban, M., Goris, A., Lorentzen, Å. et al. Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor. Eur J Hum Genet 17, 1309–1313 (2009). https://doi.org/10.1038/ejhg.2009.41
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DOI: https://doi.org/10.1038/ejhg.2009.41
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