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Genome-Wide Meta-Analysis Identifies Novel Multiple Sclerosis Susceptibility Loci
journal contribution
posted on 2023-05-17, 10:48 authored by Patsopoulos, NA, de Bakker, PI, Esposito, F, Reischl, J, Lehr, S, Bauer, D, Heubach, J, Sandbrink, R, Pohl, C, Edan, G, Kappos, L, Miller, D, Montalban, 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, Simon James FooteSimon James Foote, 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, Jim Stankovich, Stewart, GJ, Bruce TaylorBruce Taylor, 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, DAObjective: 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 = 1.6 x 10-8) near EOMES, rs2150702G in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 x 10-8), and rs6718520A 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.
History
Publication title
Annals of NeurologyVolume
70Issue
6Pagination
897-912ISSN
0364-5134Department/School
Menzies Institute for Medical ResearchPublisher
Wiley-LissPlace of publication
Div John Wiley & Sons Inc, 605 Third Ave, New York, USA, Ny, 10158-0012Rights statement
The definitive published version is available online at: http://www3.interscience.wiley.com/Repository Status
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