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

TY - JOUR

T1 - MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis

AU - Lill, Christina M

AU - Schjeide, Brit-Maren M

AU - Graetz, Christine

AU - Ban, Maria

AU - Alcina, Antonio

AU - Ortiz, Miguel A

AU - Pérez, Jennifer

AU - Damotte, Vincent

AU - Booth, David

AU - Lopez de Lapuente, Aitzkoa

AU - Broer, Linda

AU - Schilling, Marcel

AU - Akkad, Denis A

AU - Aktas, Orhan

AU - Alloza, Iraide

AU - Antigüedad, Alfredo

AU - Arroyo, Rafa

AU - Blaschke, Paul

AU - Buttmann, Mathias

AU - Chan, Andrew

AU - Compston, Alastair

AU - Cournu-Rebeix, Isabelle

AU - Dörner, Thomas

AU - Epplen, Joerg T

AU - Fernández, Óscar

AU - Gerdes, Lisa-Ann

AU - Guillot-Noël, Léna

AU - Hartung, Hans-Peter

AU - Hoffjan, Sabine

AU - Izquierdo, Guillermo

AU - Kemppinen, Anu

AU - Kroner, Antje

AU - Kubisch, Christian

AU - Kümpfel, Tania

AU - Li, Shu-Chen

AU - Lindenberger, Ulman

AU - Lohse, Peter

AU - Lubetzki, Catherine

AU - Luessi, Felix

AU - Malhotra, Sunny

AU - Mescheriakova, Julia

AU - Montalban, Xavier

AU - Papeix, Caroline

AU - Paredes, Lidia F

AU - Rieckmann, Peter

AU - Steinhagen-Thiessen, Elisabeth

AU - Winkelmann, Alexander

AU - Zettl, Uwe K

AU - Hintzen, Rogier

AU - Vandenbroeck, Koen

AU - Stewart, Graeme

AU - Fontaine, Bertrand

AU - Comabella, Manuel

AU - Urcelay, Elena

AU - Matesanz, Fuencisla

AU - Sawcer, Stephen

AU - Bertram, Lars

AU - Zipp, Frauke

AU - International Multiple Sclerosis Genetics Consortium (IMSGC)

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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.

AB - 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.

KW - Case-Control Studies

KW - Databases, Genetic

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Humans

KW - Male

KW - Multiple Sclerosis

KW - Polymorphism, Single Nucleotide

KW - Receptors, CXCR5

KW - Ribosomal Protein S6 Kinases, 70-kDa

KW - SOXE Transcription Factors

KW - Transcription Factors

KW - alpha-Mannosidase

U2 - 10.1093/brain/awt101

DO - 10.1093/brain/awt101

M3 - SCORING: Journal article

C2 - 23739915

VL - 136

SP - 1778

EP - 1782

JO - BRAIN

JF - BRAIN

SN - 0006-8950

IS - Pt 6

ER -