Genome-wide significant association with seven novel multiple sclerosis risk loci

CM Lill, F Luessi, A Alcina, EA Sokolova, N Ugidos, B de la Hera, L Guillot-Noel, S (Sunny) Malhotra, E Reinthaler, BMM Schjeide, Julia Mescheriakova, A Mashychev, I Wohlers, DA Akkad, O Aktas, I Alloza, A Antiguedad, R Arroyo, I Astobiza, P BlaschkeAN Boyko, M Buttmann, A Chan, T Dorner, JT Epplen, OO Favorova, M Fedetz, O Fernandez, A Garcia-Martinez, LA Gerdes, C Graetz, HP Hartung, S Hoffjan, G Izquierdo, DS Korobko, A Kroner, C Kubisch, T Kumpfel, L Leyva, P Lohse, NA Malkova, X Montalban, EV Popova, P Rieckmann, AS Rozhdestvenskii, C Schmied, IV Smagina, EY Tsareva, A Winkelmann, UK Zettl, H Binder, I Cournu-Rebeix, Rogier Hintzen, A Zimprich, M Comabella, B Fontaine, E Urcelay, K Vandenbroeck, M Filipenko, F Matesanz, F Zipp, L Bertram

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32 Citations (Scopus)

Abstract

Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5x10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03x10(-12)), CD28 (rs6435203, p=1.35x10(-9)), LPP (rs4686953, p=3.35x10(-8)), ETS1 (rs3809006, p=7.74x10(-9)), DLEU1 (rs806349, p=8.14x10(-12)), LPIN3 (rs6072343, p=7.16x10(-12)) and IFNGR2 (rs9808753, p=4.40x10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.
Original languageEnglish
Pages (from-to)848-855
Number of pages8
JournalJournal of Medical Genetics
Volume52
Issue number12
DOIs
Publication statusPublished - 2015

Research programs

  • EMC MM-02-72-02

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