Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array.
Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10(-5) . The effect of nine SNPs in the HLA region remained (P < 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations.
Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Theresa
T
Dankowski
Department of Neurology, Technische Universität München, Munich, Germany.
Dorothea
D
Buck
Max-Planck-Institut für Psychiatrie, Munich, Germany.
Till F M
TF
Andlauer
Central Information Office (CIO), Philipps University Marburg, Marburg, Germany.
Gisela
G
Antony
Department of Neurology, Klinikum Augsburg, Augsburg, Germany.
Antonios
A
Bayas
Department of Neurology, University of Leipzig, Leipzig, Germany.|Institute of Medical Microbiology, Otto-von-Guericke University, Magdeburg, Germany.
Lukas
L
Bechmann
Department of Neurology, Technische Universität München, Munich, Germany.
Achim
A
Berthele
Max-Planck-Institut für Psychiatrie, Munich, Germany.
Thomas
T
Bettecken
Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany.
Andrew
A
Chan
Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel, Germany.
Andre
A
Franke
Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany.
Ralf
R
Gold
Department of Neurology, University Medical Center Mainz, Mainz, Germany.
Christiane
C
Graetz
Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
Jürgen
J
Haas
Department of Neurology, University of Rostock, Rostock, Germany.
Michael
M
Hecker
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital, Basel, Switzerland.|Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
Stefan
S
Herms
Department of Neurology, Charité University Medicine Berlin, Berlin, Germany.
Carmen
C
Infante-Duarte
Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Karl-Heinz
KH
Jöckel
Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.
Bernd C
BC
Kieseier
Department of Neurology, Technische Universität München, Munich, Germany.
Benjamin
B
Knier
Department of Neurology, MPI of Psychiatry, Munich, Germany.
Matthias
M
Knop
Institute of Clinical Neuroimmunology, Ludwigs-Maximilians-Universität, Munich, Germany.
Tania
T
Kümpfel
Institute of Human Genetics, Technische Universität München, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Peter
P
Lichtner
Institute of Epidemiology and Biobank popgen, Christian-Albrechts-Universität Kiel, Kiel, Germany.
Wolfgang
W
Lieb
Department of Neurology, University Medical Center Mainz, Mainz, Germany.|Platform for Genome Analytics, Institutes of Neurogenetics, & for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
Christina M
CM
Lill
Department of Neurology, Hospital Köln-Merheim, Köln, Germany.
Volker
V
Limmroth
Department of Neurology, University Hospital Erlangen, Erlangen, Germany.
Ralf A
RA
Linker
Department of Neurology, Technische Universität München, Munich, Germany.
Verena
V
Loleit
Department für Neurologie, Klinik für Allgemeine Neurologie, Münster, Germany.
Sven G
SG
Meuth
Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Susanne
S
Moebus
Max-Planck-Institut für Psychiatrie, Munich, Germany.
Bertram
B
Müller-Myhsok
Department of Neurology, MPI of Psychiatry, Munich, Germany.
Sandra
S
Nischwitz
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Markus M
MM
Nöthen
Department of Neurology, Charité University Medicine Berlin, Berlin, Germany.|NeuroCure Clinical Research Center, Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and, Charité Universitätsmedizin Berlin, Berlin, Germany.
Friedemann
F
Paul
Department of Neurology, Philipps-University of Marburg, Marburg, Germany.
Michael
M
Pütz
Department für Neurologie, Klinik für Allgemeine Neurologie, Münster, Germany.
Tobias
T
Ruck
Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany.
Anke
A
Salmen
Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
Martin
M
Stangel
Department of Neurology and, Institute of Neuroimmunology and MS (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Jan-Patrick
JP
Stellmann
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
Konstantin
K
Strauch
Department of Neurology and, Institute of Neuroimmunology and MS (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Klarissa H
KH
Stürner
Department of Neurology, Philipps-University of Marburg, Marburg, Germany.
Björn
B
Tackenberg
Department of Neurology and Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany.
Florian
F
Then Bergh
Department of Neurology, University of Ulm, Ulm, Germany.
Hayrettin
H
Tumani
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Melanie
M
Waldenberger
Department of Neurology, MPI of Psychiatry, Munich, Germany.|Neurological Clinic, Medical Park, Bad Camberg, Germany.
Frank
F
Weber
Department für Neurologie, Klinik für Allgemeine Neurologie, Münster, Germany.
Heinz
H
Wiendl
Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
Brigitte
B
Wildemann
Department of Neurology, University of Rostock, Rostock, Germany.
Uwe K
UK
Zettl
Department of Neurology, University Hospital, Eberhard-Karls-Universität Tübingen, Tübingen, Germany.
Ulf
U
Ziemann
Department of Neurology, University Medical Center Mainz, Mainz, Germany.
Frauke
F
Zipp
Department of Neurology, Technische Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Bernhard
B
Hemmer
Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.|Zentrum für Klinische Studien, Universität zu Lübeck, Lübeck, Germany.|School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa.
Andreas
A
Ziegler
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
D006680:HLA Antigens
ANKRD55 gene; HLA-DPB2 gene; Illumina exome array; MMEL1 gene; genome-wide association study; multiple sclerosis