title: Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci.
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.
authors.affiliation: Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. pdejager@rics.bwh.harvard.edu
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Jia
authors.forename: Joanne
authors.initials: J
authors.lastname: Wang
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Linda
authors.initials: L
authors.lastname: Ottoboni
authors.forename: Neelum T
authors.initials: NT
authors.lastname: Aggarwal
authors.forename: Laura
authors.initials: L
authors.lastname: Piccio
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Dong
authors.initials: D
authors.lastname: Tran
authors.forename: Cristin
authors.initials: C
authors.lastname: Aubin
authors.forename: Rebeccah
authors.initials: R
authors.lastname: Briskin
authors.forename: Susan
authors.initials: S
authors.lastname: Romano
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Jacob L
authors.initials: JL
authors.lastname: McCauley
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gibson
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Naeglin
authors.forename: Bernard
authors.initials: B
authors.lastname: Uitdehaag
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.forename: Chris
authors.initials: C
authors.lastname: Polman
authors.forename: Wendy L
authors.initials: WL
authors.lastname: McArdle
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.forename: Denis
authors.initials: D
authors.lastname: Evans
authors.forename: Anne H
authors.initials: AH
authors.lastname: Cross
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawcer
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D000099185:Interferon Regulatory Factor-8
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D050835:Interferon Regulatory Factors; D047888:Receptors, Tumor Necrosis Factor, Type I; D000099185:Interferon Regulatory Factor-8; C062279:CD6 antigen; C506235:TNFRSF1A protein, human