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De Jager PL, Jia X, Wang J et al.Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41:776-782

Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
Nature Genetics (Impact Factor: 29.35). 08/2009; 41(7):776-82. DOI: 10.1038/ng.401
Source: PubMed

ABSTRACT

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

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    • "In conclusion, while combining datasets by imputation can lead to a more powerful GWAS (Becker et al., 2009; Hao et al., 2009) by allowing successful identification of SNPs associated with various phenotypes (Sanna et al., 2008; Willer et al., 2008; Zeggini et al., 2008; De Jager et al., 2009), the described decrease in signal inherent to imputation can partially offset any gain in power resulting from the combination of studies. Important implications of this finding include the fact that some truly associated variants may not be detected, and that some genomewide significant findings may have larger true effect sizes than estimated. "
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    • "Furthermore, a single nucleotide polymorphism (SNP) identified in the largest MS genome-wide association study [41], has recently been reported as occurring in the TNFRSF1A gene, that encodes TNFR1, and has been shown to be associated with an increased susceptibility to MS development. It is now understood that this SNP results in the expression of a soluble form of TNFR1, which can block pan TNF signalling [42]. "
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