Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

Philip L. De Jager, Xiaoming Jia, Joanne Wang, Paul I W De Bakker, Linda Ottoboni, Neelum T. Aggarwal, Laura Piccio, Soumya Raychaudhuri, Dong Tran, Cristin Aubin, Rebeccah Briskin, Susan Romano, Sergio E. Baranzini, Jacob L. McCauley, Margaret A. Pericak-Vance, Jonathan L. Haines, Rachel A. Gibson, Yvonne Naeglin, Bernard Uitdehaag, Paul M. MatthewsLudwig Kappos, Chris Polman, Wendy L. McArdle, David P. Strachan, Denis Evans, Anne H. Cross, Mark J. Daly, Alastair Compston, Stephen J. Sawcer, Howard L. Weiner, Stephen L. Hauser, David A. Hafler, Jorge R. Oksenberg

Research output: Contribution to journalArticle

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 × 10 11), IRF8 (P = 3.73 × 10 9) and CD6 (P = 3.79 × 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.

Original languageEnglish
Pages (from-to)776-782
Number of pages7
JournalNature Genetics
Volume41
Issue number7
DOIs
Publication statusPublished - Jul 2009

ASJC Scopus subject areas

  • Genetics

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    De Jager, P. L., Jia, X., Wang, J., De Bakker, P. I. W., Ottoboni, L., Aggarwal, N. T., Piccio, L., Raychaudhuri, S., Tran, D., Aubin, C., Briskin, R., Romano, S., Baranzini, S. E., McCauley, J. L., Pericak-Vance, M. A., Haines, J. L., Gibson, R. A., Naeglin, Y., Uitdehaag, B., ... Oksenberg, J. R. (2009). Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature Genetics, 41(7), 776-782. https://doi.org/10.1038/ng.401