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Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.

Authors :
Patsopoulos NA
Esposito F
Reischl J
Lehr S
Bauer D
Heubach J
Sandbrink R
Pohl C
Edan G
Kappos L
Miller D
Montalbán J
Polman CH
Freedman MS
Hartung HP
Arnason BG
Comi G
Cook S
Filippi M
Goodin DS
Jeffery D
O'Connor P
Ebers GC
Langdon D
Reder AT
Traboulsee A
Zipp F
Schimrigk S
Hillert J
Bahlo M
Booth DR
Broadley S
Brown MA
Browning BL
Browning SR
Butzkueven H
Carroll WM
Chapman C
Foote SJ
Griffiths L
Kermode AG
Kilpatrick TJ
Lechner-Scott J
Marriott M
Mason D
Moscato P
Heard RN
Pender MP
Perreau VM
Perera D
Rubio JP
Scott RJ
Slee M
Stankovich J
Stewart GJ
Taylor BV
Tubridy N
Willoughby E
Wiley J
Matthews P
Boneschi FM
Compston A
Haines J
Hauser SL
McCauley J
Ivinson A
Oksenberg JR
Pericak-Vance M
Sawcer SJ
De Jager PL
Hafler DA
de Bakker PI
Source :
Annals of neurology [Ann Neurol] 2011 Dec; Vol. 70 (6), pp. 897-912.
Publication Year :
2011

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.<br />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.<br />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).<br />Interpretation: 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.<br /> (Copyright © 2011 American Neurological Association.)

Details

Language :
English
ISSN :
1531-8249
Volume :
70
Issue :
6
Database :
MEDLINE
Journal :
Annals of neurology
Publication Type :
Academic Journal
Accession number :
22190364
Full Text :
https://doi.org/10.1002/ana.22609