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Nat Genet. 2015 Oct;47(10):1107-1113. doi: 10.1038/ng.3395. Epub 2015 Sep 7.

Class II HLA interactions modulate genetic risk for multiple sclerosis.

Author information

1
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
2
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.
3
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
4
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
5
Program in Translational NeuroPsychiatric Genomics, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
6
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.
7
Harvard Medical School, Boston, Massachusetts, USA.
8
Program in Medical and Population Genetics, Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.
9
Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.
10
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
11
Department of Neurology, University of California, San Francisco, Sandler Neurosciences Center, San Francisco, California, USA.
12
HLA Laboratory, Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
13
Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
14
Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
15
Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway.
16
Department of Neurology and Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
17
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
18
Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
19
Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
20
Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.
21
INSERM, Université Pierre et Marie Curie, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Département des Maladies du Système Nerveux and UMRS 1127-7225, Institut Cerveau Moelle Spinal Cord and Brain Institute, Pitié-Salpêtrière, Paris, France.
22
Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University-Medical Center, Mainz, Germany.
23
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
24
German Competence Network Multiple Sclerosis (KKNMS), Munich, Germany.
25
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
26
Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia.
27
Department of Mathematics and Statistics, University of Melbourne, Parkville, Melbourne, Victoria, Australia.
28
Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
29
Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
30
Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
31
Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Copenhagen, Denmark.
32
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
33
Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
34
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
35
Institut für Humangenetik, Technische Universität München, Munich, Germany.
36
Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.
37
Department of Neurology and Neurological Sciences, Center for Sleep Sciences and Medicine, Stanford University, Stanford, California, USA.
38
Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
39
Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.
40
Harvard NeuroDiscovery Center, Harvard Medical School, Boston, Massachusetts, USA.
41
University of Oslo, Oslo, Norway.
#
Contributed equally

Abstract

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.

PMID:
26343388
PMCID:
PMC4874245
DOI:
10.1038/ng.3395
[Indexed for MEDLINE]
Free PMC Article
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