Leppa, International Multiple Sclerosis Genetics Consortium V., Surakka, I., Tienari, P. J., Elovaara, I., Compston, A., Sawcer, S., Robertson, N., De Jager, P. L., Aubin, C., Hafler, D. A., Oturai, A. B., Sondergaard, H. B., Sellebjerg, F., Sorensen, P. S., Hemmer, B., Cepok, S., Winkelmann, J., Wichmann, H. E., Comabella, M., Bustamante, M. F., Montalban, X., Olsson, T., Kockum, I., Hillert, J., Alfredsson, L., Goris, A., Dubois, B., Mero, I. L., Smestad, C., Celius, E. G., Harbo, H. F., D'Alfonso, S., Bergamaschi, L., Leone, M., Ristori, Giovanni, Kappos, L., Hauser, S. L., Cournu Rebeix, I., Fontaine, B., Boonen, S., Polman, C., Palotie, A., Peltonen, L., Saarela, J., Harvard University--MIT Division of Health Sciences and Technology, Hafler, David A., Neurology, and NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases
Background In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin. Principal Findings We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19×10−7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35×10−10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19×10−5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios). Conclusions Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis., United States. National Institutes of Health (grant RO1 NS 43559), United States. National Institutes of Health (grant RO1 NS049477), Academy of Finland. Center of Excellence for Complex Disease Genetics (grant 213506), Academy of Finland. Center of Excellence for Complex Disease Genetics (grant 129680), Sigrid Jusélius stiftelse, Biocentrum Helsinki Foundation, Helsinki University. Central Hospital Research Foundation, Neuropromise EU project (grant LSHM-CT-2005-018637), Wellcome Trust (London, England) (grant 089061/Z/09/Z), Cambridge NIHR Biomedical Research Centre, The Danish Council for Strategic Research (grant 2142-08-0039), Italian Foundation for Multiple Sclerosis (FISM grants 2008/R/11), Regione Piemonte Ricerca Sanitaria Finalizzata (2007, 2008), Fondazione Cariplo (grant n° 2010- 0728), Italian Ministry of Health, CRT Foundation, National Multiple Sclerosis Society (U.S.), Swiss Multiple Sclerosis Society, United States. National Institutes of Health (R01 NS067305)