title: Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.
abstract: OBJECTIVE
  To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci.
  
  
  METHODS
  We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease.
  
  
  RESULTS
  We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1).
  
  
  CONCLUSIONS
  We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.forename: Federica
authors.initials: F
authors.lastname: Esposito
authors.forename: Joachim
authors.initials: J
authors.lastname: Reischl
authors.forename: Stephan
authors.initials: S
authors.lastname: Lehr
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Heubach
authors.forename: Rupert
authors.initials: R
authors.lastname: Sandbrink
authors.forename: Christoph
authors.initials: C
authors.lastname: Pohl
authors.forename: Gilles
authors.initials: G
authors.lastname: Edan
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.forename: Javier
authors.initials: J
authors.lastname: Montalbán
authors.forename: Chris H
authors.initials: CH
authors.lastname: Polman
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Barry G W
authors.initials: BG
authors.lastname: Arnason
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Stuart
authors.initials: S
authors.lastname: Cook
authors.forename: Massimo
authors.initials: M
authors.lastname: Filippi
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Goodin
authors.forename: Douglas
authors.initials: D
authors.lastname: Jeffery
authors.forename: Paul
authors.initials: P
authors.lastname: O'Connor
authors.forename: George C
authors.initials: GC
authors.lastname: Ebers
authors.forename: Dawn
authors.initials: D
authors.lastname: Langdon
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Reder
authors.forename: Anthony
authors.initials: A
authors.lastname: Traboulsee
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schimrigk
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
authors.forename: Simon
authors.initials: S
authors.lastname: Broadley
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Brian L
authors.initials: BL
authors.lastname: Browning
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Browning
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
authors.forename: William M
authors.initials: WM
authors.lastname: Carroll
authors.forename: Caron
authors.initials: C
authors.lastname: Chapman
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foote
authors.forename: Lyn
authors.initials: L
authors.lastname: Griffiths
authors.forename: Allan G
authors.initials: AG
authors.lastname: Kermode
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Kilpatrick
authors.forename: Jeanette
authors.initials: J
authors.lastname: Lechner-Scott
authors.forename: Mark
authors.initials: M
authors.lastname: Marriott
authors.forename: Deborah
authors.initials: D
authors.lastname: Mason
authors.forename: Pablo
authors.initials: P
authors.lastname: Moscato
authors.forename: Robert N
authors.initials: RN
authors.lastname: Heard
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pender
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Perreau
authors.forename: Devindri
authors.initials: D
authors.lastname: Perera
authors.forename: Justin P
authors.initials: JP
authors.lastname: Rubio
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.forename: Mark
authors.initials: M
authors.lastname: Slee
authors.forename: Jim
authors.initials: J
authors.lastname: Stankovich
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Stewart
authors.forename: Bruce V
authors.initials: BV
authors.lastname: Taylor
authors.forename: Niall
authors.initials: N
authors.lastname: Tubridy
authors.forename: Ernest
authors.initials: E
authors.lastname: Willoughby
authors.forename: James
authors.initials: J
authors.lastname: Wiley
authors.forename: Paul
authors.initials: P
authors.lastname: Matthews
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Boneschi
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Jonathan
authors.initials: J
authors.lastname: Haines
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Jacob
authors.initials: J
authors.lastname: McCauley
authors.forename: Adrian
authors.initials: A
authors.lastname: Ivinson
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Margaret
authors.initials: M
authors.lastname: Pericak-Vance
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawcer
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D004198:Disease Susceptibility; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D009103:Multiple Sclerosis / Q000209:etiology / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide