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A recent genome-wide association study reported five loci for which there was strong, but sub-genome-wide significant evidence for association with multiple sclerosis risk. The aim of this study was to evaluate the role of these potential risk loci in a large and independent data set of ≈ 20,000 subjects. We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent. In addition, we assessed the overall evidence for association by combining these newly generated data with the results from the original genome-wide association study by meta-analysis. All five tested single nucleotide polymorphisms showed consistent and statistically significant evidence for association with multiple sclerosis in our validation data sets (rs228614: odds ratio = 0.91, P = 2.4 × 10(-6); rs630923: odds ratio = 0.89, P = 1.2 × 10(-4); rs2744148: odds ratio = 1.14, P = 1.8 × 10(-6); rs180515: odds ratio = 1.12, P = 5.2 × 10(-7); rs6062314: odds ratio = 0.90, P = 4.3 × 10(-3)). Combining our data with results from the previous genome-wide association study by meta-analysis, the evidence for association was strengthened further, surpassing the threshold for genome-wide significance (P < 5 × 10(-8)) in each case. Our study provides compelling evidence that these five loci are genuine multiple sclerosis susceptibility loci. These results may eventually lead to a better understanding of the underlying disease pathophysiology.

Citation

International Multiple Sclerosis Genetics Consortium, Christina M Lill, Brit-Maren M Schjeide, Christine Graetz, Maria Ban, Antonio Alcina, Miguel A Ortiz, Jennifer Pérez, Vincent Damotte, David Booth, Aitzkoa Lopez de Lapuente, Linda Broer, Marcel Schilling, Denis A Akkad, Orhan Aktas, Iraide Alloza, Alfredo Antigüedad, Rafa Arroyo, Paul Blaschke, Mathias Buttmann, Andrew Chan, Alastair Compston, Isabelle Cournu-Rebeix, Thomas Dörner, Joerg T Epplen, Óscar Fernández, Lisa-Ann Gerdes, Léna Guillot-Noël, Hans-Peter Hartung, Sabine Hoffjan, Guillermo Izquierdo, Anu Kemppinen, Antje Kroner, Christian Kubisch, Tania Kümpfel, Shu-Chen Li, Ulman Lindenberger, Peter Lohse, Catherine Lubetzki, Felix Luessi, Sunny Malhotra, Julia Mescheriakova, Xavier Montalban, Caroline Papeix, Lidia F Paredes, Peter Rieckmann, Elisabeth Steinhagen-Thiessen, Alexander Winkelmann, Uwe K Zettl, Rogier Hintzen, Koen Vandenbroeck, Graeme Stewart, Bertrand Fontaine, Manuel Comabella, Elena Urcelay, Fuencisla Matesanz, Stephen Sawcer, Lars Bertram, Frauke Zipp. MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis. Brain : a journal of neurology. 2013 Jun;136(Pt 6):1778-82

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PMID: 23739915

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