Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.
Patsopoulos NA., Bayer Pharma MS Genetics Working Group None., Steering Committees of Studies Evaluating IFNβ-1b and a CCR1-Antagonist None., ANZgene Consortium None., GeneMSA None., International Multiple Sclerosis Genetics Consortium None., 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.
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 < 1 × 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.