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Genome-Wide Meta-Analysis Identifies Novel Multiple Sclerosis Susceptibility Loci


Patsopoulos, NA and de Bakker, PI and Esposito, F and Reischl, J and Lehr, S and Bauer, D and Heubach, J and Sandbrink, R and Pohl, C and Edan, G and Kappos, L and Miller, D and Montalban, J and Polman, CH and Freedman, MS and Hartung, HP and Arnason, BG and Comi, G and Cook, S and Filippi, M and Goodin, DS and Jeffery, D and O'Connor, P and Ebers, GC and Langdon, D and Reder, AT and Traboulsee, A and Zipp, F and Schimrigk, S and Hillert, J and Bahlo, M and Booth, DR and Broadley, S and Brown, MA and Browning, BL and Browning, SR and Butzkueven, H and Carroll, WM and Chapman, C and Foote, SJ and Griffiths, L and Kermode, AG and Kilpatrick, TJ and Lechner-Scott, J and Marriott, M and Mason, D and Moscato, P and Heard, RN and Pender, MP and Perreau, VM and Perera, D and Rubio, JP and Scott, RJ and Slee, M and Stankovich, J and Stewart, GJ and Taylor, BV and Tubridy, N and Willoughby, E and Wiley, J and Matthews, P and Boneschi, FM and Compston, A and Haines, J and Hauser, SL and McCauley, J and Ivinson, A and Oksenberg, JR and Pericak-Vance, M and Sawcer, SJ and De Jager, PL and Hafler, DA, Baya Pharma MS Genetics Working Group, Steering Committees of Studies Evaluating IFNB-1b and a CCR1-Antagonist; ANZgene Consortium; GeneMSA; International Multiple Sclerosis Genetics Consortium, Genome-Wide Meta-Analysis Identifies Novel Multiple Sclerosis Susceptibility Loci, Annals of Neurology, 70, (6) pp. 897-912. ISSN 0364-5134 (2011) [Refereed Article]

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DOI: doi:10.1002/ana.22609


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: rs170934T at 3p24.1 (odds ratio [OR], 1.17; p Ό 1.6  108) near EOMES, rs2150702G in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p Ό 3.3  108), and rs6718520A in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p Ό 3.4  108). 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  106, some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). 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.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Central nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Foote, SJ (Professor Simon Foote)
UTAS Author:Perera, D (Miss Devindri Perera)
UTAS Author:Stankovich, J (Dr Jim Stankovich)
UTAS Author:Taylor, BV (Professor Bruce Taylor)
ID Code:76296
Year Published:2011
Web of Science® Times Cited:242
Deposited By:Menzies Institute for Medical Research
Deposited On:2012-03-04
Last Modified:2017-11-06

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