New Results
The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility
International Multiple Sclerosis Genetics Consortium, NA Patsopoulos, SE Baranzini, A Santaniello, P Shoostari, C Cotsapas, G Wong, AH Beecham, T James, J Replogle, I Vlachos, C McCabe, T Pers, A Brandes, C White, B Keenan, M Cimpean, P Winn, IP Panteliadis, A Robbins, TFM Andlauer, O Zarzycki, B Dubois, A Goris, H Bach Sondergaard, F Sellebjerg, P Soelberg Sorensen, H Ullum, L Wegner Thoerner, J Saarela, I Cournu Rebeix, V Damotte, B Fontaine, L Guillot Noel, M Lathrop, S Vukusik, A Berthele, V Biberacher, D Buck, C Gasperi, C Graetz, V Grummel, B Hemmer, M Hoshi, B Knier, T Korn, CM Lill, F Luessi, M Mühlau, F Zipp, E Dardiotis, C Agliardi, A Amoroso, N Barizzone, MD Benedetti, L Bernardinelli, P Cavalla, F Clarelli, G Comi, D Cusi, F Esposito, L Ferrè, D Galimberti, C Guaschino, MA Leone, V Martinelli, L Moiola, M Salvetti, M Sorosina, D Vecchio, A Zauli, S Santoro, M Zuccalà, J Mescheriakova, C van Duijn, SD Bos, EG Celius, A Spurkland, M Comabella, X Montalban, L Alfredsson, I Bomfim, D Gomez-Cabrero, J Hillert, M Jagodic, M Lindén, F Piehl, I Jelčić, R Martin, M Sospedra, A Baker, M Ban, C Hawkins, P Hysi, S Kalra, F Karpe, J Khadake, G Lachance, P Molyneux, M Neville, J Thorpe, E Bradshaw, SJ Caillier, P Calabresi, BAC Cree, A Cross, M Davis, PWI de Bakker, S Delgado, M Dembele, K Edwards, K Fitzgerald, IY Frohlich, PA Gourraud, JL Haines, H Hakonarson, D Kimbrough, N Isobe, I Konidari, E Lathi, MH Lee, T Li, D An, A Zimmer, A Lo, L Madireddy, CP Manrique, M Mitrovic, M Olah, E Patrick, MA Pericak-Vance, L Piccio, C Schaefer, H Weiner, K Lage, A Compston, D Hafler, HF Harbo, SL Hauser, G Stewart, S D’Alfonso, G Hadjigeorgiou, B Taylor, LF Barcellos, D Booth, R Hintzen, I Kockum, F Martinelli-Boneschi, JL McCauley, JR Oksenberg, A Oturai, S Sawcer, AJ Ivinson, T Olsson, PL De Jager, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederick Colombe, Mario Cottone, Anthony Croft, Renata D’Incà, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas A Kennedy, Mohammed Azam Khan, Marc Lémann, Arie Levine, Dunecan Massey, Monica Milla, Grant W Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah D. Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M Taylor, Leif Törkvist, Kullak Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H. Vatn, Hu Zhang, Wei Zhang, Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium
doi: https://doi.org/10.1101/143933
1Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham & Women's Hospital, Boston, 02115 MA, USA
- For correspondence: pld2115@cumc.columbia.edu
NA Patsopoulos
1Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham & Women's Hospital, Boston, 02115 MA, USA
2Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
3Harvard Medical School, Boston, MA 02115, USA
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
SE Baranzini
5Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
A Santaniello
5Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
P Shoostari
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
6Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
7Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
C Cotsapas
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
6Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
7Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
G Wong
1Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham & Women's Hospital, Boston, 02115 MA, USA
3Harvard Medical School, Boston, MA 02115, USA
AH Beecham
8John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
T James
9Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
J Replogle
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
I Vlachos
1Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham & Women's Hospital, Boston, 02115 MA, USA
3Harvard Medical School, Boston, MA 02115, USA
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
C McCabe
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
T Pers
11The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark
A Brandes
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
C White
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
B Keenan
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
M Cimpean
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
P Winn
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
IP Panteliadis
1Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham & Women's Hospital, Boston, 02115 MA, USA
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
A Robbins
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
TFM Andlauer
12Max Planck Institute of Psychiatry, 80804 Munich, Germany
13Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
O Zarzycki
1Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham & Women's Hospital, Boston, 02115 MA, USA
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
B Dubois
14Laboratory for Neuroimmunology, Section of Experimental Neurology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
A Goris
14Laboratory for Neuroimmunology, Section of Experimental Neurology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
H Bach Sondergaard
15Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Section 6311, 2100 Copenhagen, Denmark
F Sellebjerg
15Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Section 6311, 2100 Copenhagen, Denmark
P Soelberg Sorensen
15Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Section 6311, 2100 Copenhagen, Denmark
H Ullum
16Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Section 2082, 2100 Copenhagen, Denmark
L Wegner Thoerner
16Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Section 2082, 2100 Copenhagen, Denmark
J Saarela
17Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
I Cournu Rebeix
18INSERM UMR S 975 CRICM, UPMC, Departement de Neurologie Pitie-Salpetriere, AP-HP 75013 PARIS, France
V Damotte
18INSERM UMR S 975 CRICM, UPMC, Departement de Neurologie Pitie-Salpetriere, AP-HP 75013 PARIS, France
B Fontaine
18INSERM UMR S 975 CRICM, UPMC, Departement de Neurologie Pitie-Salpetriere, AP-HP 75013 PARIS, France
L Guillot Noel
18INSERM UMR S 975 CRICM, UPMC, Departement de Neurologie Pitie-Salpetriere, AP-HP 75013 PARIS, France
M Lathrop
19Commissariat à l′Energie Atomique, Institut Genomique, Centre National de Génotypage, Evry, France
20Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain, Paris, France
21McGill University and Genome Quebec Innovation Center, Montreal, Canada
S Vukusik
18INSERM UMR S 975 CRICM, UPMC, Departement de Neurologie Pitie-Salpetriere, AP-HP 75013 PARIS, France
A Berthele
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
V Biberacher
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
D Buck
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
C Gasperi
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
C Graetz
23Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University-Medical Center, Mainz, Germany
V Grummel
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
B Hemmer
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
24Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
25German competence network for multiple sclerosis
M Hoshi
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
B Knier
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
T Korn
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
24Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
25German competence network for multiple sclerosis
CM Lill
26Department of Neurology, Focus Program Translational Neuroscience (FTN), and Immunology (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
27Genetic and Molecular Epidemiology Group, Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
F Luessi
26Department of Neurology, Focus Program Translational Neuroscience (FTN), and Immunology (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
M Mühlau
22Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strasse 22, 81675 Munich, Germany
F Zipp
26Department of Neurology, Focus Program Translational Neuroscience (FTN), and Immunology (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
E Dardiotis
28Neurology Dpt, Neurogenetics Lab, University Hospital of Larissa, Greece
C Agliardi
29Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi Foundation ONLUS, IRCCS S. Maria Nascente, Milan, Italy
A Amoroso
30Department of Medical Sciences, Torino University, Turin, Italy
N Barizzone
31Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy
MD Benedetti
32Centro Regionale Sclerosi Multipla, Neurologia B, AOUI Verona, Italy
33Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Italy
L Bernardinelli
34Medical Research Council Biostatistics Unit, Robinson Way, Cambridge CB2 0SR, UK
P Cavalla
35MS Center, Department of Neuroscience, A.O. Città della Salute e della Scienza di Torino & University of Turin, Torino, Italy
F Clarelli
36Laboratory of Human Genetics of Neurological complex disorder, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
G Comi
36Laboratory of Human Genetics of Neurological complex disorder, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
37Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
D Cusi
38University of Milan, Department of Health Sciences, San Paolo Hospital and Filarete Foundation, viale Ortles 22/4, 20139 Milan, Italy
F Esposito
36Laboratory of Human Genetics of Neurological complex disorder, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
39Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
L Ferrè
39Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
D Galimberti
40Neurology Unit, Dept. of Pathophysiology and Transplantation, University of Milan
C Guaschino
36Laboratory of Human Genetics of Neurological complex disorder, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
39Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
MA Leone
41Department of Neurology, Ospedale Maggiore, Novara, Italy
V Martinelli
39Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
L Moiola
39Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
M Salvetti
42Center for Experimental Neurological Therapy (CENTERS), Neurology and Department of Neurosciences, Mental Health and Sensory Organs, Università La Sapienza, Roma, Italy
M Sorosina
36Laboratory of Human Genetics of Neurological complex disorder, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
D Vecchio
41Department of Neurology, Ospedale Maggiore, Novara, Italy
A Zauli
36Laboratory of Human Genetics of Neurological complex disorder, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
S Santoro
36Laboratory of Human Genetics of Neurological complex disorder, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
M Zuccalà
43Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy
J Mescheriakova
44Department of Neurology, Erasmus MC, Rotterdam, Netherlands
C van Duijn
44Department of Neurology, Erasmus MC, Rotterdam, Netherlands
SD Bos
45Department of Neurology, Institute of Clinical Medicine, University of Oslo, Norway
EG Celius
46Department of Neurology, Oslo University Hospital, Oslo, Norway
A Spurkland
47Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
M Comabella
48Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Spain
X Montalban
48Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Spain
L Alfredsson
49Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
I Bomfim
50Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
D Gomez-Cabrero
50Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
J Hillert
50Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
M Jagodic
50Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
M Lindén
50Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
F Piehl
50Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
I Jelčić
51Neuroimmunology and MS Research (nims), Neurology Clinic, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland
52Department of Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zürich, Frauenklinikstrasse 26, 8091 Zürich, Switzerland
R Martin
51Neuroimmunology and MS Research (nims), Neurology Clinic, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland
52Department of Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zürich, Frauenklinikstrasse 26, 8091 Zürich, Switzerland
M Sospedra
51Neuroimmunology and MS Research (nims), Neurology Clinic, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland
52Department of Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zürich, Frauenklinikstrasse 26, 8091 Zürich, Switzerland
A Baker
53University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, BOX 165, Hills Road, Cambridge CB2 0QQ, UK
M Ban
53University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, BOX 165, Hills Road, Cambridge CB2 0QQ, UK
C Hawkins
54Keele University Medical School, University Hospital of North Staffordshire, Stoke-on-Trent ST4 7NY, UK
P Hysi
55Department of Twin Research and Genetic Epidemiology, King’s College London, London, SE1 7EH, UK
S Kalra
54Keele University Medical School, University Hospital of North Staffordshire, Stoke-on-Trent ST4 7NY, UK
F Karpe
56Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
J Khadake
57NIHR BioResource, Box 299,University of Cambridge and Cambridge University Hospitals NHS Foundation Trust Hills Road, Cambridge CB2 0QQ, UK
G Lachance
55Department of Twin Research and Genetic Epidemiology, King’s College London, London, SE1 7EH, UK
P Molyneux
53University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, BOX 165, Hills Road, Cambridge CB2 0QQ, UK
M Neville
56Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
J Thorpe
58Department of Neurology, Peterborough City Hospital, Edith Cavell Campus, Bretton Gate, Peterborough PE3 9GZ, UK
E Bradshaw
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
SJ Caillier
5Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
P Calabresi
59Department of Neurology, Johns Hopkins University School of medicine, Baltimore MD
BAC Cree
5Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
A Cross
60Multiple sclerosis center, Department of neurology, School of medicine, Washington University St Louis, St Louis MO
M Davis
61Center for Human Genetics Research, Vanderbilt University Medical Center, 525 Light Hall, 2215 Garland Avenue, Nashville, TN 37232, USA
PWI de Bakker
2Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
3Harvard Medical School, Boston, MA 02115, USA
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
S Delgado
62Multiple Sclerosis Division, Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
M Dembele
59Department of Neurology, Johns Hopkins University School of medicine, Baltimore MD
K Edwards
63MS Center of Northeastern NY 1205 Troy Schenectady Rd, Latham, NY 12110
K Fitzgerald
59Department of Neurology, Johns Hopkins University School of medicine, Baltimore MD
IY Frohlich
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
PA Gourraud
5Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
64ITUN - CRTI - UMR Inserm 1064 - Nantes University and Hopsitals, France
JL Haines
65Population & Quantitative Health Sciences, Department of Epidemiology and Biostatistics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4945 USA
H Hakonarson
66Center for Applied Genomics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA
67Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
D Kimbrough
68Department of Neurology, Brigham & Women's Hospital, Boston, 02115 MA, USA
N Isobe
5Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
I Konidari
8John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
E Lathi
69The Elliot Lewis Center, 110 Cedar St, Wellesley MA, 02481, USA
MH Lee
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
T Li
70Broad Institute of Harvard University and MIT, Cambridge, 02142 MA, USA
D An
70Broad Institute of Harvard University and MIT, Cambridge, 02142 MA, USA
A Zimmer
70Broad Institute of Harvard University and MIT, Cambridge, 02142 MA, USA
A Lo
71Mt. Sinai Rehab Hospital, Mandell MS Center, Hartford, CT 06112, USA
L Madireddy
5Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
CP Manrique
8John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
M Mitrovic
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
6Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
7Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
M Olah
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
E Patrick
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
MA Pericak-Vance
8John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
L Piccio
60Multiple sclerosis center, Department of neurology, School of medicine, Washington University St Louis, St Louis MO
C Schaefer
72Kaiser Permanente Division of Research, Oakland, CA, USA
H Weiner
73Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham & Women's Hospital, Boston, 02115 MA, USA
K Lage
70Broad Institute of Harvard University and MIT, Cambridge, 02142 MA, USA
A Compston
53University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, BOX 165, Hills Road, Cambridge CB2 0QQ, UK
D Hafler
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
74Departments of Neurology and Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
HF Harbo
45Department of Neurology, Institute of Clinical Medicine, University of Oslo, Norway
46Department of Neurology, Oslo University Hospital, Oslo, Norway
SL Hauser
5Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
G Stewart
75Westmead Millennium Institute, University of Sydney, New South Wales, Australia
S D’Alfonso
76Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy
G Hadjigeorgiou
28Neurology Dpt, Neurogenetics Lab, University Hospital of Larissa, Greece
B Taylor
77Menzies Research Institute Tasmania, University of Tasmania, Australia
LF Barcellos
78UC Berkeley School of Public Health and Center for Computational Biology, USA
D Booth
79Westmead Millennium Institute, University of Sydney, New South Wales, Australia
R Hintzen
80Department of Neurology and Department of Immunology, Erasmus MC, Rotterdam, Netherlands
I Kockum
9Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
F Martinelli-Boneschi
36Laboratory of Human Genetics of Neurological complex disorder, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
37Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
JL McCauley
8John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
JR Oksenberg
5Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
A Oturai
15Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Section 6311, 2100 Copenhagen, Denmark
S Sawcer
53University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, BOX 165, Hills Road, Cambridge CB2 0QQ, UK
AJ Ivinson
81BWH Institute for the Neurosciences and the Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Boston, 02115 MA, USA
T Olsson
9Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
PL De Jager
4Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
10Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA
Murray Barclay
1Department of Medicine, University of Otago, Christchurch, New Zealand
Laurent Peyrin-Biroulet
2Gastroenterology Unit, INSERM U954, Nancy University and Hospital, France
Mathias Chamaillard
3INSERM, U1019, Lille, France
Jean-Frederick Colombe
4Univ Lille Nord de France, CHU Lille and Lille-2 University, Gastroenterology Unit, France
Mario Cottone
5Division of Internal Medicine, Villa Sofia-V. Cervello Hospital, University of Palermo, Palermo, Italy
Anthony Croft
6Inflammatory Bowel Diseases, Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia
Renata D’Incà
7Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy
Jonas Halfvarson
8Department of Medicine, Örebro University Hospital, Örebro, Sweden
9School of Health and Medical Sciences, Örebro University, Örebro, Sweden
Katherine Hanigan
6Inflammatory Bowel Diseases, Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia
Paul Henderson
10Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Edinburgh, UK
11Child Life and Health, University of Edinburgh, Edinburgh, UK
Jean-Pierre Hugot
12INSERM U843, Paris, France
13Univ-Paris Diderot Sorbonne Paris-Cité, Paris France
Amir Karban
14Department of Gastroenterology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Nicholas A Kennedy
15Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
Mohammed Azam Khan
16Genetic Medicine, MAHSC, University of Manchester, Manchester, UK
Marc Lémann
17Université Paris Diderot, GETAID group, Paris, France
Arie Levine
18Pediatric Gastroenterology Unit, Wolfson Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Dunecan Massey
19Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
Monica Milla
20Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy
Grant W Montgomery
21Molecular Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia
Sok Meng Evelyn Ng
22Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
Ioannis Oikonomou
22Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
Harald Peeters
23Dept Gastroenterology - University hospital Gent - De Pintelaan - 9000 Gent Belgium
Deborah D. Proctor
22Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
Jean-Francois Rahier
24Dept Gastroenterology - UCL Mont Godinne Belgium
Rebecca Roberts
2Gastroenterology Unit, INSERM U954, Nancy University and Hospital, France
Paul Rutgeerts
25Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
Frank Seibold
26University of Bern, Division of Gastroenterology, Inselspital, Bern
Laura Stronati
3INSERM, U1019, Lille, France
Kirstin M Taylor
28Neurology Dpt, Neurogenetics Lab, University Hospital of Larissa, Greece
Leif Törkvist
1Department of Medicine, University of Otago, Christchurch, New Zealand
Kullak Ublick
2Gastroenterology Unit, INSERM U954, Nancy University and Hospital, France
Johan Van Limbergen
3INSERM, U1019, Lille, France
Andre Van Gossum
4Univ Lille Nord de France, CHU Lille and Lille-2 University, Gastroenterology Unit, France
Morten H. Vatn
5Division of Internal Medicine, Villa Sofia-V. Cervello Hospital, University of Palermo, Palermo, Italy
Hu Zhang
20Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy
Wei Zhang
22Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- For correspondence: pld2115@cumc.columbia.edu
Abstract:
We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.
One Sentence Summary: We report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
Posted July 13, 2017.
The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility
International Multiple Sclerosis Genetics Consortium, NA Patsopoulos, SE Baranzini, A Santaniello, P Shoostari, C Cotsapas, G Wong, AH Beecham, T James, J Replogle, I Vlachos, C McCabe, T Pers, A Brandes, C White, B Keenan, M Cimpean, P Winn, IP Panteliadis, A Robbins, TFM Andlauer, O Zarzycki, B Dubois, A Goris, H Bach Sondergaard, F Sellebjerg, P Soelberg Sorensen, H Ullum, L Wegner Thoerner, J Saarela, I Cournu Rebeix, V Damotte, B Fontaine, L Guillot Noel, M Lathrop, S Vukusik, A Berthele, V Biberacher, D Buck, C Gasperi, C Graetz, V Grummel, B Hemmer, M Hoshi, B Knier, T Korn, CM Lill, F Luessi, M Mühlau, F Zipp, E Dardiotis, C Agliardi, A Amoroso, N Barizzone, MD Benedetti, L Bernardinelli, P Cavalla, F Clarelli, G Comi, D Cusi, F Esposito, L Ferrè, D Galimberti, C Guaschino, MA Leone, V Martinelli, L Moiola, M Salvetti, M Sorosina, D Vecchio, A Zauli, S Santoro, M Zuccalà, J Mescheriakova, C van Duijn, SD Bos, EG Celius, A Spurkland, M Comabella, X Montalban, L Alfredsson, I Bomfim, D Gomez-Cabrero, J Hillert, M Jagodic, M Lindén, F Piehl, I Jelčić, R Martin, M Sospedra, A Baker, M Ban, C Hawkins, P Hysi, S Kalra, F Karpe, J Khadake, G Lachance, P Molyneux, M Neville, J Thorpe, E Bradshaw, SJ Caillier, P Calabresi, BAC Cree, A Cross, M Davis, PWI de Bakker, S Delgado, M Dembele, K Edwards, K Fitzgerald, IY Frohlich, PA Gourraud, JL Haines, H Hakonarson, D Kimbrough, N Isobe, I Konidari, E Lathi, MH Lee, T Li, D An, A Zimmer, A Lo, L Madireddy, CP Manrique, M Mitrovic, M Olah, E Patrick, MA Pericak-Vance, L Piccio, C Schaefer, H Weiner, K Lage, A Compston, D Hafler, HF Harbo, SL Hauser, G Stewart, S D’Alfonso, G Hadjigeorgiou, B Taylor, LF Barcellos, D Booth, R Hintzen, I Kockum, F Martinelli-Boneschi, JL McCauley, JR Oksenberg, A Oturai, S Sawcer, AJ Ivinson, T Olsson, PL De Jager, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederick Colombe, Mario Cottone, Anthony Croft, Renata D’Incà, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas A Kennedy, Mohammed Azam Khan, Marc Lémann, Arie Levine, Dunecan Massey, Monica Milla, Grant W Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah D. Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M Taylor, Leif Törkvist, Kullak Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H. Vatn, Hu Zhang, Wei Zhang, Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium
bioRxiv 143933; doi: https://doi.org/10.1101/143933
The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility
International Multiple Sclerosis Genetics Consortium, NA Patsopoulos, SE Baranzini, A Santaniello, P Shoostari, C Cotsapas, G Wong, AH Beecham, T James, J Replogle, I Vlachos, C McCabe, T Pers, A Brandes, C White, B Keenan, M Cimpean, P Winn, IP Panteliadis, A Robbins, TFM Andlauer, O Zarzycki, B Dubois, A Goris, H Bach Sondergaard, F Sellebjerg, P Soelberg Sorensen, H Ullum, L Wegner Thoerner, J Saarela, I Cournu Rebeix, V Damotte, B Fontaine, L Guillot Noel, M Lathrop, S Vukusik, A Berthele, V Biberacher, D Buck, C Gasperi, C Graetz, V Grummel, B Hemmer, M Hoshi, B Knier, T Korn, CM Lill, F Luessi, M Mühlau, F Zipp, E Dardiotis, C Agliardi, A Amoroso, N Barizzone, MD Benedetti, L Bernardinelli, P Cavalla, F Clarelli, G Comi, D Cusi, F Esposito, L Ferrè, D Galimberti, C Guaschino, MA Leone, V Martinelli, L Moiola, M Salvetti, M Sorosina, D Vecchio, A Zauli, S Santoro, M Zuccalà, J Mescheriakova, C van Duijn, SD Bos, EG Celius, A Spurkland, M Comabella, X Montalban, L Alfredsson, I Bomfim, D Gomez-Cabrero, J Hillert, M Jagodic, M Lindén, F Piehl, I Jelčić, R Martin, M Sospedra, A Baker, M Ban, C Hawkins, P Hysi, S Kalra, F Karpe, J Khadake, G Lachance, P Molyneux, M Neville, J Thorpe, E Bradshaw, SJ Caillier, P Calabresi, BAC Cree, A Cross, M Davis, PWI de Bakker, S Delgado, M Dembele, K Edwards, K Fitzgerald, IY Frohlich, PA Gourraud, JL Haines, H Hakonarson, D Kimbrough, N Isobe, I Konidari, E Lathi, MH Lee, T Li, D An, A Zimmer, A Lo, L Madireddy, CP Manrique, M Mitrovic, M Olah, E Patrick, MA Pericak-Vance, L Piccio, C Schaefer, H Weiner, K Lage, A Compston, D Hafler, HF Harbo, SL Hauser, G Stewart, S D’Alfonso, G Hadjigeorgiou, B Taylor, LF Barcellos, D Booth, R Hintzen, I Kockum, F Martinelli-Boneschi, JL McCauley, JR Oksenberg, A Oturai, S Sawcer, AJ Ivinson, T Olsson, PL De Jager, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederick Colombe, Mario Cottone, Anthony Croft, Renata D’Incà, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas A Kennedy, Mohammed Azam Khan, Marc Lémann, Arie Levine, Dunecan Massey, Monica Milla, Grant W Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah D. Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M Taylor, Leif Törkvist, Kullak Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H. Vatn, Hu Zhang, Wei Zhang, Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium
bioRxiv 143933; doi: https://doi.org/10.1101/143933
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