Abstract
A recent genome-wide association study by the International Multiple Sclerosis Genetics Consortium (IMSGC) reported association of 17 single-nucleotide polymorphisms (SNPs) in 14 loci with multiple sclerosis (MS). Only two loci, HLA-DRA and IL2RA, reached genome-wide significance (P<5E−08). In our study, we determined whether we could replicate the results of the IMSGC and whether more SNPs are genome-wide significantly associated with MS. We assessed the association between the 17 IMSGC SNPs and MS in three cohorts (total number of subjects 3981, among these 1853 cases). We performed a meta-analysis of the results of our study, the original IMSGC results and the results of a recent replication study performed in the Australian population. Of the 17 IMSGC SNPs, five SNPs showed genome-wide significant association with MS: HLA-DRA (P=8E−124), IL7R (P=6E−09), IL2RA (P=1E−11), CD58 (P=4E−09) and CLEC16A (P=3E−12). Therefore, genome-wide significance has now been shown for SNPs in different non-HLA MS risk genes. Several of these risk genes, including CD58 and CLEC16A, are shared by different autoimmune diseases. Fine mapping studies will be needed to determine the functional contributions to distinct autoimmune phenotypes.
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Acknowledgements
This study was supported by grants from MS Research Netherlands (RQH and CvD), the Netherlands Organisation for Scientific Research (ZON-MW, RQH), Erasmus MC and the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom (SVR, GCE). The GRIP study is supported by Centre for Medical Systems Biology (CMSB). We are grateful to all patients and their relatives, general practitioners and neurologists for their contributions and to P Veraart, genealogist in the GRIP area, for her help in genealogy. D Lont and the personnel of the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be/) for genotyping and P Snijders, general practitioner in the GRIP area, for his help in data collection. Our study complies with the current laws of the countries in which they were performed.
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Hoppenbrouwers, I., Aulchenko, Y., Janssens, A. et al. Replication of CD58 and CLEC16A as genome-wide significant risk genes for multiple sclerosis. J Hum Genet 54, 676–680 (2009). https://doi.org/10.1038/jhg.2009.96
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DOI: https://doi.org/10.1038/jhg.2009.96
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