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

• Published in: Nature genetics Vol. 41; no. 7; pp. 776 - 782
• Main Authors: De Jager, Philip L, Jia, Xiaoming, Wang, Joanne, de Bakker, Paul I W, Ottoboni, Linda, Aggarwal, Neelum T, Piccio, Laura, Raychaudhuri, Soumya, Tran, Dong, Aubin, Cristin, Briskin, Rebeccah, Romano, Susan, Baranzini, Sergio E, McCauley, Jacob L, Pericak-Vance, Margaret A, Haines, Jonathan L, Gibson, Rachel A, Naeglin, Yvonne, Uitdehaag, Bernard, Matthews, Paul M, Kappos, Ludwig, Polman, Chris, McArdle, Wendy L, Strachan, David P, Evans, Denis, Cross, Anne H, Daly, Mark J, Compston, Alastair, Sawcer, Stephen J, Weiner, Howard L, Hauser, Stephen L, Hafler, David A, Oksenberg, Jorge R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2009; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Antigens, CD - genetics; Antigens, Differentiation, T-Lymphocyte - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; Case-Control Studies; Data base management; DNA replication; Fundamental and applied biological sciences. Psychology; Gene Function; Gene loci; Genetic aspects; Genetic Predisposition to Disease; Genetic susceptibility; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Heart attacks; Human Genetics; Humans; Inflammatory diseases; Inflation; Interferon Regulatory Factors - genetics; Medical sciences; Meta-analysis; Methods; Molecular and cellular biology; Molecular genetics; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurological disorders; Neurology; Oligonucleotide Array Sequence Analysis; Physiological aspects; Receptors, Tumor Necrosis Factor, Type I - genetics; Regression analysis; Replication; Risk factors; Stratigraphy; United States; United Kingdom; Nervous system diseases; Multiple sclerosis; Central nervous system disease; Replication; Identification; Genome; Locus; Inflammatory disease; Metaanalysis
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.401

Philip De Jager and colleagues report results of a large genome-wide association and replication study for multiple sclerosis. The work uncovers three new susceptibility loci for MS, including common and rare variants at TNFRSF1A and common variants at IRF8 and CD6 . 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.