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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.

The Genetic Association of Variants in CD6, TNFRSF1A and IRF8 to Multiple Sclerosis: A Multicenter Case-Control Study