Class II HLA interactions modulate genetic risk for multiple sclerosis.
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.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Loukas
L
Moutsianas
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Luke
L
Jostins
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Ashley H
AH
Beecham
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Alexander T
AT
Dilthey
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Dionysia K
DK
Xifara
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Maria
M
Ban
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Tejas S
TS
Shah
Program in Translational NeuroPsychiatric Genomics, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.
Nikolaos A
NA
Patsopoulos
Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.
Lars
L
Alfredsson
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Carl A
CA
Anderson
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Katherine E
KE
Attfield
Department of Neurology, University of California, San Francisco, Sandler Neurosciences Center, San Francisco, California, USA.
Sergio E
SE
Baranzini
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Jeffrey
J
Barrett
HLA Laboratory, Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Thomas M C
TMC
Binder
Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
David
D
Booth
Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
Dorothea
D
Buck
Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway.
Elisabeth G
EG
Celius
Program in Medical and Population Genetics, Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.|Department of Neurology and Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
Chris
C
Cotsapas
Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Sandra
S
D'Alfonso
Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Calliope A
CA
Dendrou
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Peter
P
Donnelly
Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.
Bénédicte
B
Dubois
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.
Bertrand
B
Fontaine
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.|Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Lars
L
Fugger
Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.
An
A
Goris
Department of Neurology, University of California, San Francisco, Sandler Neurosciences Center, San Francisco, California, USA.
Pierre-Antoine
PA
Gourraud
Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University-Medical Center, Mainz, Germany.
Christiane
C
Graetz
Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|German Competence Network Multiple Sclerosis (KKNMS), Munich, Germany.
Bernhard
B
Hemmer
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Jan
J
Hillert
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Ingrid
I
Kockum
Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia.|Department of Mathematics and Statistics, University of Melbourne, Parkville, Melbourne, Victoria, Australia.
Stephen
S
Leslie
Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University-Medical Center, Mainz, Germany.|Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
Christina M
CM
Lill
Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.|Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Filippo
F
Martinelli-Boneschi
Department of Neurology, University of California, San Francisco, Sandler Neurosciences Center, San Francisco, California, USA.
Jorge R
JR
Oksenberg
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Tomas
T
Olsson
Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Copenhagen, Denmark.
Annette
A
Oturai
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Janna
J
Saarela
Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Copenhagen, Denmark.
Helle Bach
HB
Søndergaard
Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Anne
A
Spurkland
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
Bruce
B
Taylor
Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|Institut für Humangenetik, Technische Universität München, Munich, Germany.|Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.|Department of Neurology and Neurological Sciences, Center for Sleep Sciences and Medicine, Stanford University, Stanford, California, USA.
Juliane
J
Winkelmann
Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University-Medical Center, Mainz, Germany.
Frauke
F
Zipp
Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Jonathan L
JL
Haines
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Margaret A
MA
Pericak-Vance
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Chris C A
CCA
Spencer
Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
Graeme
G
Stewart
Program in Medical and Population Genetics, Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.|Department of Neurology and Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.|Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.
David A
DA
Hafler
Harvard NeuroDiscovery Center, Harvard Medical School, Boston, Massachusetts, USA.
Adrian J
AJ
Ivinson
Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway.|University of Oslo, Oslo, Norway.
Hanne F
HF
Harbo
Department of Neurology, University of California, San Francisco, Sandler Neurosciences Center, San Francisco, California, USA.
Stephen L
SL
Hauser
Program in Translational NeuroPsychiatric Genomics, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.
Philip L
PL
De Jager
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Alastair
A
Compston
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Jacob L
JL
McCauley
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Stephen
S
Sawcer
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Gil
G
McVean
D000483:Alleles; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D000949:Histocompatibility Antigens Class II