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Genet Epidemiol. 2015 Dec;39(8):601-8. doi: 10.1002/gepi.21933. Epub 2015 Oct 26.

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array.

Author information

1
Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
2
Department of Neurology, Technische Universität München, Munich, Germany.
3
Max-Planck-Institut für Psychiatrie, Munich, Germany.
4
Central Information Office (CIO), Philipps University Marburg, Marburg, Germany.
5
Department of Neurology, Klinikum Augsburg, Augsburg, Germany.
6
Department of Neurology, University of Leipzig, Leipzig, Germany.
7
Institute of Medical Microbiology, Otto-von-Guericke University, Magdeburg, Germany.
8
Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany.
9
Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel, Germany.
10
Department of Neurology, University Medical Center Mainz, Mainz, Germany.
11
Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
12
Department of Neurology, University of Rostock, Rostock, Germany.
13
Institute of Human Genetics, University of Bonn, Bonn, Germany.
14
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
15
Division of Medical Genetics, University Hospital, Basel, Switzerland.
16
Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
17
Department of Neurology, Charité University Medicine Berlin, Berlin, Germany.
18
Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
19
Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.
20
Department of Neurology, MPI of Psychiatry, Munich, Germany.
21
Institute of Clinical Neuroimmunology, Ludwigs-Maximilians-Universität, Munich, Germany.
22
Institute of Human Genetics, Technische Universität München, Munich, Germany.
23
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
24
Institute of Epidemiology and Biobank popgen, Christian-Albrechts-Universität Kiel, Kiel, Germany.
25
Platform for Genome Analytics, Institutes of Neurogenetics, & for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
26
Department of Neurology, Hospital Köln-Merheim, Köln, Germany.
27
Department of Neurology, University Hospital Erlangen, Erlangen, Germany.
28
Department für Neurologie, Klinik für Allgemeine Neurologie, Münster, Germany.
29
NeuroCure Clinical Research Center, Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and, Charité Universitätsmedizin Berlin, Berlin, Germany.
30
Department of Neurology, Philipps-University of Marburg, Marburg, Germany.
31
Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
32
Department of Neurology and, Institute of Neuroimmunology and MS (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
33
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
34
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
35
Department of Neurology and Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany.
36
Department of Neurology, University of Ulm, Ulm, Germany.
37
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
38
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
39
Neurological Clinic, Medical Park, Bad Camberg, Germany.
40
Department of Neurology, University Hospital, Eberhard-Karls-Universität Tübingen, Tübingen, Germany.
41
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
42
Zentrum für Klinische Studien, Universität zu Lübeck, Lübeck, Germany.
43
School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa.

Abstract

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.

KEYWORDS:

ANKRD55 gene; HLA-DPB2 gene; Illumina exome array; MMEL1 gene; genome-wide association study; multiple sclerosis

PMID:
26497834
DOI:
10.1002/gepi.21933
[Indexed for MEDLINE]

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