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Ann Neurol DOI:10.1002/ana.22609

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

Publication TypeJournal Article
Year of Publication2011
AuthorsPatsopoulos, 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, H-P, Arnason, BGW, 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, PIW
Corporate AuthorsBayer Pharma MS Genetics Working Group, Steering Committees of Studies Evaluating IFNβ-1b and a CCR1-Antagonist, ANZgene Consortium, GeneMSA, International Multiple Sclerosis Genetics Consortium
JournalAnn Neurol
Volume70
Issue6
Pages897-912
Date Published2011 Dec
ISSN1531-8249
KeywordsAdolescent, Adult, Child, Disease Susceptibility, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Meta-Analysis as Topic, Middle Aged, Multiple Sclerosis, Odds Ratio, Polymorphism, Single Nucleotide, Young Adult
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

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.

URLhttp://dx.doi.org/10.1002/ana.22609
DOI10.1002/ana.22609
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22190364?dopt=Abstract

Alternate JournalAnn. Neurol.
PubMed ID22190364
PubMed Central IDPMC3247076
Grant ListU01 MH46276 / MH / NIMH NIH HHS / United States
R01 HG004960 / HG / NHGRI NIH HHS / United States
R01 MH60879 / MH / NIMH NIH HHS / United States
R01 MH59566 / MH / NIMH NIH HHS / United States
U01 MH79470 / MH / NIMH NIH HHS / United States
R01 NS049477 / NS / NINDS NIH HHS / United States
R01MH81800 / MH / NIMH NIH HHS / United States
RC2 NS070340 / NS / NINDS NIH HHS / United States
R01 MH59588 / MH / NIMH NIH HHS / United States
R01 MH59586 / MH / NIMH NIH HHS / United States
R01 MH59587 / MH / NIMH NIH HHS / United States
R01 NS067305 / NS / NINDS NIH HHS / United States
R01 MH59565 / MH / NIMH NIH HHS / United States
R01 MH61675 / MH / NIMH NIH HHS / United States
P01 AI039671 / AI / NIAID NIH HHS / United States
U01 MH46289 / MH / NIMH NIH HHS / United States
R01 MH59571 / MH / NIMH NIH HHS / United States
U01 MH79469 / MH / NIMH NIH HHS / United States
R01 MH67257 / MH / NIMH NIH HHS / United States
R01 NS067305-01 / NS / NINDS NIH HHS / United States
068545/Z/02 / / Wellcome Trust / United Kingdom
U01 MH46318 / MH / NIMH NIH HHS / United States
R01 MH60870 / MH / NIMH NIH HHS / United States
G0000934 / / Medical Research Council / United Kingdom
RC2 NS070340-01 / NS / NINDS NIH HHS / United States