期刊
ANNALS OF NEUROLOGY
卷 70, 期 6, 页码 897-912出版社
WILEY
DOI: 10.1002/ana.22609
关键词
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资金
- National MS Society
- NIH [R01 NS067305, RC2 NS070340]
- Multiple Sclerosis Research Australia
- John T. Reid Charitable Trusts
- Trish MS Research Foundation
- Australian Research Council [LP0776744]
- NIH National Heart, Lung, and Blood Institute
- National Center for Research Resources
- Medical Research Council [G0000934]
- Wellcome Trust [068545/Z/02]
- MRC [G0000934] Funding Source: UKRI
- Australian Research Council [LP0776744] Funding Source: Australian Research Council
- Medical Research Council [G0000934] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10335] Funding Source: researchfish
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 x 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 x 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 x 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 x 10(-6), 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. ANN NEUROL 2011; 70: 897-912
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