title: MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis.
abstract: 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.
authors.affiliation: Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Christina M
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authors.lastname: Lill
authors.forename: Brit-Maren M
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authors.lastname: Schjeide
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authors.lastname: Graetz
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authors.forename: David
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authors.lastname: Lopez de Lapuente
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authors.forename: Andrew
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authors.forename: Isabelle
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authors.lastname: Cournu-Rebeix
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authors.lastname: Gerdes
authors.forename: Léna
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authors.lastname: Guillot-Noël
authors.forename: Hans-Peter
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authors.lastname: Hartung
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authors.forename: Guillermo
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authors.lastname: Izquierdo
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authors.forename: Antje
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authors.lastname: Kümpfel
authors.forename: Shu-Chen
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authors.forename: Ulman
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authors.lastname: Lindenberger
authors.forename: Peter
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authors.lastname: Lohse
authors.forename: Catherine
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authors.lastname: Lubetzki
authors.forename: Felix
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authors.lastname: Luessi
authors.forename: Sunny
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authors.lastname: Malhotra
authors.forename: Julia
authors.initials: J
authors.lastname: Mescheriakova
authors.forename: Xavier
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authors.lastname: Montalban
authors.forename: Caroline
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authors.lastname: Papeix
authors.forename: Lidia F
authors.initials: LF
authors.lastname: Paredes
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authors.lastname: Rieckmann
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steinhagen-Thiessen
authors.forename: Alexander
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authors.lastname: Winkelmann
authors.forename: Uwe K
authors.initials: UK
authors.lastname: Zettl
authors.forename: Rogier
authors.initials: R
authors.lastname: Hintzen
authors.forename: Koen
authors.initials: K
authors.lastname: Vandenbroeck
authors.forename: Graeme
authors.initials: G
authors.lastname: Stewart
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Matesanz
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.forename: Lars
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authors.forename: Frauke
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authors.lastname: Zipp
mesh_terms: D016022:Case-Control Studies; D030541:Databases, Genetic; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054380:Receptors, CXCR5 / Q000235:genetics*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics*; D055757:SOXE Transcription Factors / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D043323:alpha-Mannosidase / Q000235:genetics*
chemical_list: C095085:CXCR5 protein, human; D054380:Receptors, CXCR5; C406240:SOX8 protein, human; D055757:SOXE Transcription Factors; D014157:Transcription Factors; C574225:Zbtb46 protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D043323:alpha-Mannosidase
keywords: complex genetics; genetic association; genetic risk; immunogenetics; multiple sclerosis