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MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis

Lill, Christina M ; Schjeide, Brit-Maren M ; Graetz, Christine ; Ban, Maria ; Alcina, Antonio ; Ortiz, Miguel A ; Pérez, Jennifer ; Damotte, Vincent ; Booth, David and Lopez de Lapuente, Aitzkoa LU , et al. (2013) In Brain : a journal of neurology 136(Pt 6). p.82-1778
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... (More)

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.

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publishing date
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Contribution to journal
publication status
published
subject
keywords
Case-Control Studies, Databases, Genetic, Female, Genetic Loci/genetics, Genetic Predisposition to Disease/genetics, Humans, Male, Multiple Sclerosis/diagnosis, Polymorphism, Single Nucleotide/genetics, Receptors, CXCR5/genetics, Ribosomal Protein S6 Kinases, 70-kDa/genetics, SOXE Transcription Factors/genetics, Transcription Factors/genetics, alpha-Mannosidase/genetics
in
Brain : a journal of neurology
volume
136
issue
Pt 6
pages
5 pages
publisher
Oxford University Press
external identifiers
  • pmid:23739915
  • scopus:84878863691
ISSN
1460-2156
DOI
10.1093/brain/awt101
language
English
LU publication?
no
id
3eaaa124-9613-4756-ae87-75f7e04c168a
date added to LUP
2021-01-17 18:58:23
date last changed
2022-11-23 19:56:48
@article{3eaaa124-9613-4756-ae87-75f7e04c168a,
  abstract     = {{<p>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 &lt; 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.</p>}},
  author       = {{Lill, Christina M and Schjeide, Brit-Maren M and Graetz, Christine and Ban, Maria and Alcina, Antonio and Ortiz, Miguel A and Pérez, Jennifer and Damotte, Vincent and Booth, David and Lopez de Lapuente, Aitzkoa and Broer, Linda and Schilling, Marcel and Akkad, Denis A and Aktas, Orhan and Alloza, Iraide and Antigüedad, Alfredo and Arroyo, Rafa and Blaschke, Paul and Buttmann, Mathias and Chan, Andrew and Compston, Alastair and Cournu-Rebeix, Isabelle and Dörner, Thomas and Epplen, Joerg T and Fernández, Óscar and Gerdes, Lisa-Ann and Guillot-Noël, Léna and Hartung, Hans-Peter and Hoffjan, Sabine and Izquierdo, Guillermo and Kemppinen, Anu and Kroner, Antje and Kubisch, Christian and Kümpfel, Tania and Li, Shu-Chen and Lindenberger, Ulman and Lohse, Peter and Lubetzki, Catherine and Luessi, Felix and Malhotra, Sunny and Mescheriakova, Julia and Montalban, Xavier and Papeix, Caroline and Paredes, Lidia F and Rieckmann, Peter and Steinhagen-Thiessen, Elisabeth and Winkelmann, Alexander and Zettl, Uwe K and Hintzen, Rogier and Vandenbroeck, Koen}},
  issn         = {{1460-2156}},
  keywords     = {{Case-Control Studies; Databases, Genetic; Female; Genetic Loci/genetics; Genetic Predisposition to Disease/genetics; Humans; Male; Multiple Sclerosis/diagnosis; Polymorphism, Single Nucleotide/genetics; Receptors, CXCR5/genetics; Ribosomal Protein S6 Kinases, 70-kDa/genetics; SOXE Transcription Factors/genetics; Transcription Factors/genetics; alpha-Mannosidase/genetics}},
  language     = {{eng}},
  number       = {{Pt 6}},
  pages        = {{82--1778}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain : a journal of neurology}},
  title        = {{MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis}},
  url          = {{http://dx.doi.org/10.1093/brain/awt101}},
  doi          = {{10.1093/brain/awt101}},
  volume       = {{136}},
  year         = {{2013}},
}