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

Christina M. Lill*, Felix Luessi, Antonio Alcina, Ekaterina A. Sokolova, Nerea Ugidos, Belén de la Hera, Léna Guillot-Noël, Sunny Malhotra, Eva Reinthaler, Brit Maren M. Schjeide, Julia Y. Mescheriakova, Andriy Mashychev, Inken Wohlers, Denis A. Akkad, Orhan Aktas, Iraide Alloza, Alfredo Antigüedad, Rafa Arroyo, Ianire Astobiza, Paul BlaschkeAlexei N. Boyko, Mathias Buttmann, Andrew Chan, Thomas Dörner, Joerg T. Epplen, Olga O. Favorova, Maria Fedetz, Oscar Fernández, Angel García-Martínez, Lisa Ann Gerdes, Christiane Graetz, Hans Peter Hartung, Sabine Hoffjan, Guillermo Izquierdo, Denis S. Korobko, Antje Kroner, Christian Kubisch, Tania Kümpfel, Laura Leyva, Peter Lohse, Nadezhda A. Malkova, Xavier Montalban, Ekaterina V. Popova, Peter Rieckmann, Alexei S. Rozhdestvenskii, Christiane Schmied, Inna V. Smagina, Ekaterina Y. Tsareva, Alexander Winkelmann, Uwe K. Zettl, Harald Binder, Isabelle Cournu-Rebeix, Rogier Hintzen, Alexander Zimprich, Manuel Comabella, Bertrand Fontaine, Elena Urcelay, Koen Vandenbroeck, Maxim Filipenko, Fuencisla Matesanz, Frauke Zipp, Lars Bertram

*Corresponding author for this work
16 Citations (Scopus)


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 metaanalysis. 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<5×10-8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10-12), CD28 (rs6435203, p=1.35×10-9), LPP (rs4686953, p=3.35×10-8), ETS1 (rs3809006, p=7.74×10-9), DLEU1 (rs806349, p=8.14×10-12), LPIN3 (rs6072343, p=7.16×10-12) and IFNGR2 (rs9808753, p=4.40×10-10). 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
JournalJournal of Medical Genetics
Issue number12
Pages (from-to)848-855
Number of pages8
Publication statusPublished - 01.01.2015


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