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Wouter van Rheenen, Rick van der Spek, Mark Bakker, Leonard van den Berg, Jan Veldink, Joke van Vugt, Paul Hop, Ramona Zwamborn, Niek de Klein, Harm-Jan Westra, Olivier Bakker, Patrick Deelen, Gemma Shireby, Eilis Hannon, Matthieu Moisse, Denis Baird, Restuadi Restuadi, Egor Dolzhenko, Annelot Dekker, Klara Gawor, Henk-Jan Westeneng, Gijs Tazelaar, Kristel van Eijk, Maarten Kooyman, Ross Byrne, Mark Doherty, Mark Heverin, Ahmad Al Khleifat, Alfredo Iacoangeli, Aleksey Shatunov, Nicola Ticozzi, Johnathan Cooper-Knock, Bradley Smith, Marta Gromicho, Siddharthan Chandran, Suvankar Pal, Karen Morrison, Pamela Shaw, John Hardy, Richard Orrell, Michael Sendtner, Thomas Meyer, Nazli Basak, Anneke van der Kooi, Antonia Ratti, Isabella Fogh, Cinzia Gellera, Guiseppe Lauria Pinter, Stefania Corti, Cristina Cereda, Daisy Sproviero, Sandra D'Alfonso, Gianni Soraru, Gabriele Siciliano, Massimiliano Filosto, Alessandro Padovani, Adriano Chio, Andrea Calvo, Cristina Moglia, Maura Brunetti, Antonio Canosa, Maurizio Grassano, Ettore Beghi, Elisabetta Pupillo, Giancarlo Logroscino, Beatrice Nefussy, Alma Osmanovic, Angelica Nordin, Yossef Lerner, Michal Zabari, Marc Gotkine, Robert Baloh, Shaugn Bell, Patrick Vourc'h, Philippe Corcia, Philippe Couratier, Stephanie Millecamps, Vincent Meininger, Francois Salachas, Jesus Mora Pardina, Abdelilah Assialioui, Ricardo Rojas-García, Patrick Dion, Jay Ross, Albert Ludolph, Jochen Weishaupt, David Brenner, Axel Freischmidt, Gilbert Bensimon, Alexis Brice, Alexandra Durr, Christine Payan, Safa Saker-Delye, Nicholas Wood, Simon Topp, Rosa Rademakers, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Stephan Ripke, Alice Braun, Julia Kraft, David Whiteman, Catherine Olsen, André Uitterlinden, Albert Hofman, Marcella Rietschel, Sven Cichon, Markus Nöthen, Philippe Amouyel, Bryan Traynor, Andrew Singleton, Miguel Mitne Neto, Ruben Cauchi, Roel Ophoff, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna Van Deerlin, Julian Grosskreutz, Annekathrin Rödiger, Alexander Jörk, Tabea Barthel, Erik Theele, Berjamin Ilse, Beatrice Stubendorff, Otto Witte, Robert Steinbach, Christian Hübner, Caroline Graff, Lev Brylev, Vera Fominykh, Vera Demeshonok, Anastasia Ataulina, Boris Rogelj, Blaž Koritnik, Janez Zidar, Metka Ravnik-Glavač, Damjan Glavač, Zorica Stević, Vivian Drory, Mónica Povedano, Ian Blair, Matthew Kiernan, Beben Benyamin, Robert Henderson, Sarah Furlong, Susan Mathers, Pamela McCombe, Merrilee Needham, Shyuan Ngo, Garth Nicholson, Roger Pamphlett, Dominic Rowe, Frederik Steyn, Kelly Williams, Karen Mather, Perminder Sachdev, Anjali Henders, Leanne Wallace, Mamede de Carvalho, Susana Pinto, Susanne Petri, Markus Weber, Guy Rouleau, Vincenzo Silani, Charles Curtis, Gerome Breen, Jonathan Glass, Robert Brown, John Landers, Christopher Shaw, Peter Andersen, Ewout Groen, Michael van Es, Jeroen Pasterkamp, Dongsheng Fan, Fleur Garton, Allan McRae, George Davey Smith, Tom Gaunt, Michael Eberle, Jonathan Mill, Russell McLaughlin, Orla Hardiman, Kevin Kenna, Naomi Wray, Ellen Tsai, Heiko Runz, Lude Franke, Ammar Al-Chalabi, Philip Van Damme, Nayana Gaur
Wouter van Rheenen
UMC Utrecht
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5860-1533
Rick van der Spek
Brain Center Rudolf Magnus
Mark Bakker
University Medical Center Utrecht
ORCiD: https://orcid.org/0000-0002-7887-9014
Leonard van den Berg
UMC Utrecht
Jan Veldink
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht
ORCiD: https://orcid.org/0000-0001-5572-9657
Joke van Vugt
University Medical Center Utrecht
Paul Hop
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht
Ramona Zwamborn
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht
Niek de Klein
University of Groningen
ORCiD: https://orcid.org/0000-0003-4640-9904
Harm-Jan Westra
University Medical Center Groningen
ORCiD: https://orcid.org/0000-0001-7038-567X
Olivier Bakker
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
Patrick Deelen
University Medical Center Groningen
ORCiD: https://orcid.org/0000-0002-5654-3966
Gemma Shireby
University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.
Eilis Hannon
University of Exeter
ORCiD: https://orcid.org/0000-0001-6840-072X
Matthieu Moisse
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), Leuven, Belgium.
Denis Baird
Translational Biology, Biogen, Boston, Massachusetts, USA.
Restuadi Restuadi
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Egor Dolzhenko
Illumina Inc
Annelot Dekker
University Medical Center Utrecht
Klara Gawor
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht Univer
ORCiD: https://orcid.org/0000-0001-7571-5420
Henk-Jan Westeneng
University Medical Center Utrecht Brain Center, Utrecht University
Gijs Tazelaar
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht Univer
Kristel van Eijk
Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht
Maarten Kooyman
ORCiD: https://orcid.org/0000-0002-9023-5617
Ross Byrne
Trinity College Dublin
ORCiD: https://orcid.org/0000-0002-4082-6072
Mark Doherty
Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin D02 PN40, Ireland.
Mark Heverin
Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin D02 PN40, Ireland.
Ahmad Al Khleifat
Maurice Wohl Clinical Neuroscience Institute
ORCiD: https://orcid.org/0000-0002-7406-9831
Alfredo Iacoangeli
King's College London
Aleksey Shatunov
King's College London, Maurice Wohl Clinical Neuroscience Institute
Nicola Ticozzi
IRCCS Istituto Auxologico Italiano
ORCiD: https://orcid.org/0000-0001-5963-7426
Johnathan Cooper-Knock
University of Sheffield
Bradley Smith
Institute of Psychiatry, Kings College London
Marta Gromicho
Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
ORCiD: https://orcid.org/0000-0003-2111-4579
Siddharthan Chandran
University of Edinburgh
Suvankar Pal
University of Edinburgh
Karen Morrison
School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
Pamela Shaw
University of Sheffield
John Hardy
University College London
Richard Orrell
Institute of Neurology, UCL
Michael Sendtner
University Hospital Wuerrzburg
Thomas Meyer
Charité Universitätsmedizin Berlin
ORCiD: https://orcid.org/0000-0002-2736-7350
Nazli Basak
Bogazici University,
Anneke van der Kooi
Amsterdam Medical Center
Antonia Ratti
University of Milan
Isabella Fogh
King's College London, Institute of Psychiatry
Cinzia Gellera
Fondazione IRCCS Istituto Neurologico Carlo Besta
Guiseppe Lauria Pinter
3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico "Carlo Besta", MIlan, Italy.
Stefania Corti
Università degli Studi di Milano
Cristina Cereda
Fondazione Istituto Neurologico Nazionale Casimiro Mondino
Daisy Sproviero
Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.
Sandra D'Alfonso
University of Eastern Piedmont
Gianni Soraru
University of Padova, Italy
Gabriele Siciliano
University of Pisa
Massimiliano Filosto
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Alessandro Padovani
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Adriano Chio
University of Torino
Andrea Calvo
University of Torino
ORCiD: https://orcid.org/0000-0002-5122-7243
Cristina Moglia
‘Rita Levi Montalcini’ Department of Neuroscience, University of Turin
Maura Brunetti
“Rita Levi Montalcini” Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Antonio Canosa
University of Turin
Maurizio Grassano
“Rita Levi Montalcini” Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Ettore Beghi
IRCCS Istituto di Ricerche Farmacologiche Mario Negri
Elisabetta Pupillo
IRCCS Istituto di Ricerche Farmacologiche Mario Negri
Giancarlo Logroscino
Neurosciences and Sense Organs of the "Aldo Moro" University of Bari
Beatrice Nefussy
Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel.
Alma Osmanovic
Department of Neurology, Hannover Medical School, Hannover, Germany.
Angelica Nordin
Department of Clinical Sciences, Neurosciences, Umeå University, SE-901 85 Umeå, Sweden.
Yossef Lerner
Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Michal Zabari
Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Marc Gotkine
Hadassah Medical Center
Robert Baloh
Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, California, 90048, USA
Shaugn Bell
Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, California, 90048, USA
Patrick Vourc'h
Université François Rabelais
Philippe Corcia
CHU de Tours, Université François Rabelais
Philippe Couratier
Centre de compétence SLA-fédération Tours-Limoges
Stephanie Millecamps
Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127
Vincent Meininger
Hôpital des Peupliers, Ramsay Générale de Santé, 75013 Paris, France.
Francois Salachas
APHP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Centre référent SLA
Jesus Mora Pardina
Hospital Universitario San Rafael
Abdelilah Assialioui
L'Hospitalet de Llobregat
Ricardo Rojas-García
Hospital de la Santa Creu i Sant Pau de Barcelona
ORCiD: https://orcid.org/0000-0003-1411-5573
Patrick Dion
McGill University
Jay Ross
McGill University
ORCiD: https://orcid.org/0000-0002-8183-2524
Albert Ludolph
German Center for Neurodegenerative Diseases
Jochen Weishaupt
Division of Neurodegeneration, Department of Neurology, University Medicine Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
David Brenner
Division of Neurodegeneration, Department of Neurology, University Medicine Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Axel Freischmidt
Department of Neurology, Ulm University, Ulm, Germany.
Gilbert Bensimon
Département de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, UPMC Pharmacologie, AP-HP, Paris, France.
Alexis Brice
INSERM U679
Alexandra Durr
INSERM
Christine Payan
AP-HP
Safa Saker-Delye
Genethon
Nicholas Wood
University College London
ORCiD: https://orcid.org/0000-0002-9500-3348
Simon Topp
King's College London
ORCiD: https://orcid.org/0000-0002-5200-3284
Rosa Rademakers
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
Lukas Tittmann
Christian-Albrechts University Kiel and Biobank popgen
Wolfgang Lieb
Institute of Epidemiology and Biobank popgen, University of Kiel
Andre Franke
Christian-Albrechts-University of Kiel
ORCiD: https://orcid.org/0000-0003-1530-5811
Stephan Ripke
Massachusetts General Hospital
Alice Braun
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin 10117, Germany.
Julia Kraft
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin 10117, Germany.
ORCiD: https://orcid.org/0000-0001-7306-1179
David Whiteman
QIMR Berghofer Medical Research Institute
ORCiD: https://orcid.org/0000-0003-2563-9559
Catherine Olsen
QIMR Berghofer Medical Research Institute
ORCiD: https://orcid.org/0000-0003-4483-1888
André Uitterlinden
Erasmus MC
ORCiD: https://orcid.org/0000-0002-7276-3387
Albert Hofman
Erasmus MC University Medical Centre Rotterdam
Marcella Rietschel
University of Mannheim
ORCiD: https://orcid.org/0000-0002-5236-6149
Sven Cichon
University of Bonn
Markus Nöthen
University of Bonn
Philippe Amouyel
Institut Pasteur de Lille
ORCiD: https://orcid.org/0000-0001-9088-234X
Bryan Traynor
National Institute on Aging
Andrew Singleton
National Institute on Aging
Miguel Mitne Neto
Fleury Group
Ruben Cauchi
Center for Molecular Medicine and Biobanking & Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Malta.
Roel Ophoff
University of California Los Angeles, University Medical Center Utrecht
Martina Wiedau-Pazos
University of California Los Angeles
Catherine Lomen-Hoerth
University of California
Vivianna Van Deerlin
University of Pennsylvania
ORCiD: https://orcid.org/0000-0002-7400-9097
Julian Grosskreutz
University Hospital Jena
Annekathrin Rödiger
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Alexander Jörk
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Tabea Barthel
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Erik Theele
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Berjamin Ilse
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Beatrice Stubendorff
University Hospital Jena
Otto Witte
Hans Berger Department of Neurology, Jena University Hospital
Robert Steinbach
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Christian Hübner
Jena University Hospital
Caroline Graff
Karolinska Institutet
Lev Brylev
Department of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Vera Fominykh
Department of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Vera Demeshonok
ALS-care center, "GAOORDI", Medical Clinic of the St. Petersburg, St. Petersburg, Russia.
Anastasia Ataulina
Department of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Boris Rogelj
Jožef Stefan Institute
ORCiD: https://orcid.org/0000-0003-3898-1943
Blaž Koritnik
Ljubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, SI-1000 Ljubljana
ORCiD: https://orcid.org/0000-0002-5083-8261
Janez Zidar
University Clinical Center Ljubljana
Metka Ravnik-Glavač
University of Ljubljana
Damjan Glavač
Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Zorica Stević
Clinic of Neurology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia
Vivian Drory
Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel.
Mónica Povedano
L'Hospitalet de Llobregat
Ian Blair
Macquarie University
Matthew Kiernan
University of Syndey
Beben Benyamin
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Robert Henderson
Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4029, Australia.
Sarah Furlong
Centre for Motor Neuron Disease Research, Macquarie University, NSW 2109, Australia.
Susan Mathers
Calvary Health Care Bethlehem, Parkdale, VIC 3195, Australia.
Pamela McCombe
Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4019, Australia.
Merrilee Needham
Fiona Stanley Hospital, Perth, WA 6150, Australia.
Shyuan Ngo
The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia.
Garth Nicholson
Macquarie University
Roger Pamphlett
The University of Sydney
ORCiD: https://orcid.org/0000-0003-3326-7273
Dominic Rowe
Centre for Motor Neuron Disease Research, Macquarie University, New South Wales 2109, Australia
ORCiD: https://orcid.org/0000-0003-0912-2146
Frederik Steyn
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Kelly Williams
Macquarie University
ORCiD: https://orcid.org/0000-0001-6319-9473
Karen Mather
Centre for Healthy Brain Ageing, Psychiatry, University of New South Wales (UNSW)
ORCiD: https://orcid.org/0000-0003-4143-8941
Perminder Sachdev
ORCiD: https://orcid.org/0000-0002-9595-3220
Anjali Henders
University of Queensland
Leanne Wallace
University of Queensland
Mamede de Carvalho
Instituto de Medicina Molecular and Institute of Physiology, Faculty of Medicine, University of Lisbon, Portugal
Susana Pinto
Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Susanne Petri
Otto-von-Guericke University Magdeburg
Markus Weber
Kantonspital St. Gallen
Guy Rouleau
Department of Human Genetics, McGill University, Montréal, QC, Canada; Montreal Neurological Institute and Hospital, McGill University, Montréal, QC
ORCiD: https://orcid.org/0000-0001-8403-1418
Vincenzo Silani
IRCCS Istituto Auxologico Italiano-University of Milan Medical School
ORCiD: https://orcid.org/0000-0002-7698-3854
Charles Curtis
King's College London
Gerome Breen
King's College London
ORCiD: https://orcid.org/0000-0003-2053-1792
Jonathan Glass
Emory University
ORCiD: https://orcid.org/0000-0002-3295-4971
Robert Brown
University of Massachusetts Medical School
John Landers
University of Massachusetts Medical School
Christopher Shaw
Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London
Peter Andersen
Umeå University
ORCiD: https://orcid.org/0000-0003-0094-5429
Ewout Groen
University Medical Center Utrecht
ORCiD: https://orcid.org/0000-0002-2330-9444
Michael van Es
University Medical Center Utrecht
ORCiD: https://orcid.org/0000-0002-7709-5883
Jeroen Pasterkamp
University Medical Center Utrecht
ORCiD: https://orcid.org/0000-0003-1631-6440
Dongsheng Fan
Peking University Third Hospital
Fleur Garton
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Allan McRae
University of Queensland
George Davey Smith
University of Bristol
ORCiD: https://orcid.org/0000-0002-1407-8314
Tom Gaunt
University of Bristol
ORCiD: https://orcid.org/0000-0003-0924-3247
Michael Eberle
Illumina Inc.
ORCiD: https://orcid.org/0000-0001-8965-1253
Jonathan Mill
University of Exeter
ORCiD: https://orcid.org/0000-0003-1115-3224
Russell McLaughlin
Trinity College Dublin
ORCiD: https://orcid.org/0000-0003-3915-2135
Orla Hardiman
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D02 PN40, Ireland.
Kevin Kenna
University Medical Center Utrecht
Naomi Wray
University of Queensland
ORCiD: https://orcid.org/0000-0001-7421-3357
Ellen Tsai
Biogen
ORCiD: https://orcid.org/0000-0002-5625-1189
Heiko Runz
Translational Genome Sciences, Biogen, 225 Binney Street, Cambridge, MA 02142, USA
Lude Franke
University Medical Center Groningen
ORCiD: https://orcid.org/0000-0002-5159-8802
Ammar Al-Chalabi
King's College London
ORCiD: https://orcid.org/0000-0002-4924-7712
Philip Van Damme
Universitaire Ziekenhuizen Leuven
ORCiD: https://orcid.org/0000-0002-4010-2357
Nayana Gaur
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
Keywords
Disease-modifying Therapies, Cross-ancestry GWAS, Cortex-derived eQTL Dataset, Mendelian Randomization Analyses, High Cholesterol Levels, Vesicle Mediated Transport
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Yes there is potential Competing Interest. J.H.V has sponsored research agreements with Biogen Idec. L.H.v.d.B receives personal fees from Cytokinetics, outside the submitted work. A.A-C. has served on scientific advisory boards for Mitsubishi Tanabe Pharma, OrionPharma, Biogen Idec, Lilly, GSK, Apellis, Amylyx, and Wave Therapeutics. A.C. serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Biogen Idec, Denali, and Cytokinetics.
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Article
Wouter van Rheenen, Rick van der Spek, Mark Bakker, Leonard van den Berg, Jan Veldink, Joke van Vugt, Paul Hop, Ramona Zwamborn, Niek de Klein, Harm-Jan Westra, Olivier Bakker, Patrick Deelen, Gemma Shireby, Eilis Hannon, Matthieu Moisse, Denis Baird, Restuadi Restuadi, Egor Dolzhenko, Annelot Dekker, Klara Gawor, Henk-Jan Westeneng, Gijs Tazelaar, Kristel van Eijk, Maarten Kooyman, Ross Byrne, Mark Doherty, Mark Heverin, Ahmad Al Khleifat, Alfredo Iacoangeli, Aleksey Shatunov, Nicola Ticozzi, Johnathan Cooper-Knock, Bradley Smith, Marta Gromicho, Siddharthan Chandran, Suvankar Pal, Karen Morrison, Pamela Shaw, John Hardy, Richard Orrell, Michael Sendtner, Thomas Meyer, Nazli Basak, Anneke van der Kooi, Antonia Ratti, Isabella Fogh, Cinzia Gellera, Guiseppe Lauria Pinter, Stefania Corti, Cristina Cereda, Daisy Sproviero, Sandra D'Alfonso, Gianni Soraru, Gabriele Siciliano, Massimiliano Filosto, Alessandro Padovani, Adriano Chio, Andrea Calvo, Cristina Moglia, Maura Brunetti, Antonio Canosa, Maurizio Grassano, Ettore Beghi, Elisabetta Pupillo, Giancarlo Logroscino, Beatrice Nefussy, Alma Osmanovic, Angelica Nordin, Yossef Lerner, Michal Zabari, Marc Gotkine, Robert Baloh, Shaugn Bell, Patrick Vourc'h, Philippe Corcia, Philippe Couratier, Stephanie Millecamps, Vincent Meininger, Francois Salachas, Jesus Mora Pardina, Abdelilah Assialioui, Ricardo Rojas-García, Patrick Dion, Jay Ross, Albert Ludolph, Jochen Weishaupt, David Brenner, Axel Freischmidt, Gilbert Bensimon, Alexis Brice, Alexandra Durr, Christine Payan, Safa Saker-Delye, Nicholas Wood, Simon Topp, Rosa Rademakers, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Stephan Ripke, Alice Braun, Julia Kraft, David Whiteman, Catherine Olsen, André Uitterlinden, Albert Hofman, Marcella Rietschel, Sven Cichon, Markus Nöthen, Philippe Amouyel, Bryan Traynor, Andrew Singleton, Miguel Mitne Neto, Ruben Cauchi, Roel Ophoff, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna Van Deerlin, Julian Grosskreutz, Annekathrin Rödiger, Alexander Jörk, Tabea Barthel, Erik Theele, Berjamin Ilse, Beatrice Stubendorff, Otto Witte, Robert Steinbach, Christian Hübner, Caroline Graff, Lev Brylev, Vera Fominykh, Vera Demeshonok, Anastasia Ataulina, Boris Rogelj, Blaž Koritnik, Janez Zidar, Metka Ravnik-Glavač, Damjan Glavač, Zorica Stević, Vivian Drory, Mónica Povedano, Ian Blair, Matthew Kiernan, Beben Benyamin, Robert Henderson, Sarah Furlong, Susan Mathers, Pamela McCombe, Merrilee Needham, Shyuan Ngo, Garth Nicholson, Roger Pamphlett, Dominic Rowe, Frederik Steyn, Kelly Williams, Karen Mather, Perminder Sachdev, Anjali Henders, Leanne Wallace, Mamede de Carvalho, Susana Pinto, Susanne Petri, Markus Weber, Guy Rouleau, Vincenzo Silani, Charles Curtis, Gerome Breen, Jonathan Glass, Robert Brown, John Landers, Christopher Shaw, Peter Andersen, Ewout Groen, Michael van Es, Jeroen Pasterkamp, Dongsheng Fan, Fleur Garton, Allan McRae, George Davey Smith, Tom Gaunt, Michael Eberle, Jonathan Mill, Russell McLaughlin, Orla Hardiman, Kevin Kenna, Naomi Wray, Ellen Tsai, Heiko Runz, Lude Franke, Ammar Al-Chalabi, Philip Van Damme, Nayana Gaur
Wouter van Rheenen
UMC Utrecht
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5860-1533
Rick van der Spek
Brain Center Rudolf Magnus
Mark Bakker
University Medical Center Utrecht
ORCiD: https://orcid.org/0000-0002-7887-9014
Leonard van den Berg
UMC Utrecht
Jan Veldink
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht
ORCiD: https://orcid.org/0000-0001-5572-9657
Joke van Vugt
University Medical Center Utrecht
Paul Hop
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht
Ramona Zwamborn
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht
Niek de Klein
University of Groningen
ORCiD: https://orcid.org/0000-0003-4640-9904
Harm-Jan Westra
University Medical Center Groningen
ORCiD: https://orcid.org/0000-0001-7038-567X
Olivier Bakker
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
Patrick Deelen
University Medical Center Groningen
ORCiD: https://orcid.org/0000-0002-5654-3966
Gemma Shireby
University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.
Eilis Hannon
University of Exeter
ORCiD: https://orcid.org/0000-0001-6840-072X
Matthieu Moisse
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), Leuven, Belgium.
Denis Baird
Translational Biology, Biogen, Boston, Massachusetts, USA.
Restuadi Restuadi
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Egor Dolzhenko
Illumina Inc
Annelot Dekker
University Medical Center Utrecht
Klara Gawor
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht Univer
ORCiD: https://orcid.org/0000-0001-7571-5420
Henk-Jan Westeneng
University Medical Center Utrecht Brain Center, Utrecht University
Gijs Tazelaar
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht Univer
Kristel van Eijk
Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht
Maarten Kooyman
ORCiD: https://orcid.org/0000-0002-9023-5617
Ross Byrne
Trinity College Dublin
ORCiD: https://orcid.org/0000-0002-4082-6072
Mark Doherty
Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin D02 PN40, Ireland.
Mark Heverin
Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin D02 PN40, Ireland.
Ahmad Al Khleifat
Maurice Wohl Clinical Neuroscience Institute
ORCiD: https://orcid.org/0000-0002-7406-9831
Alfredo Iacoangeli
King's College London
Aleksey Shatunov
King's College London, Maurice Wohl Clinical Neuroscience Institute
Nicola Ticozzi
IRCCS Istituto Auxologico Italiano
ORCiD: https://orcid.org/0000-0001-5963-7426
Johnathan Cooper-Knock
University of Sheffield
Bradley Smith
Institute of Psychiatry, Kings College London
Marta Gromicho
Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
ORCiD: https://orcid.org/0000-0003-2111-4579
Siddharthan Chandran
University of Edinburgh
Suvankar Pal
University of Edinburgh
Karen Morrison
School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
Pamela Shaw
University of Sheffield
John Hardy
University College London
Richard Orrell
Institute of Neurology, UCL
Michael Sendtner
University Hospital Wuerrzburg
Thomas Meyer
Charité Universitätsmedizin Berlin
ORCiD: https://orcid.org/0000-0002-2736-7350
Nazli Basak
Bogazici University,
Anneke van der Kooi
Amsterdam Medical Center
Antonia Ratti
University of Milan
Isabella Fogh
King's College London, Institute of Psychiatry
Cinzia Gellera
Fondazione IRCCS Istituto Neurologico Carlo Besta
Guiseppe Lauria Pinter
3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico "Carlo Besta", MIlan, Italy.
Stefania Corti
Università degli Studi di Milano
Cristina Cereda
Fondazione Istituto Neurologico Nazionale Casimiro Mondino
Daisy Sproviero
Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.
Sandra D'Alfonso
University of Eastern Piedmont
Gianni Soraru
University of Padova, Italy
Gabriele Siciliano
University of Pisa
Massimiliano Filosto
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Alessandro Padovani
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Adriano Chio
University of Torino
Andrea Calvo
University of Torino
ORCiD: https://orcid.org/0000-0002-5122-7243
Cristina Moglia
‘Rita Levi Montalcini’ Department of Neuroscience, University of Turin
Maura Brunetti
“Rita Levi Montalcini” Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Antonio Canosa
University of Turin
Maurizio Grassano
“Rita Levi Montalcini” Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Ettore Beghi
IRCCS Istituto di Ricerche Farmacologiche Mario Negri
Elisabetta Pupillo
IRCCS Istituto di Ricerche Farmacologiche Mario Negri
Giancarlo Logroscino
Neurosciences and Sense Organs of the "Aldo Moro" University of Bari
Beatrice Nefussy
Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel.
Alma Osmanovic
Department of Neurology, Hannover Medical School, Hannover, Germany.
Angelica Nordin
Department of Clinical Sciences, Neurosciences, Umeå University, SE-901 85 Umeå, Sweden.
Yossef Lerner
Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Michal Zabari
Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Marc Gotkine
Hadassah Medical Center
Robert Baloh
Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, California, 90048, USA
Shaugn Bell
Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, California, 90048, USA
Patrick Vourc'h
Université François Rabelais
Philippe Corcia
CHU de Tours, Université François Rabelais
Philippe Couratier
Centre de compétence SLA-fédération Tours-Limoges
Stephanie Millecamps
Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127
Vincent Meininger
Hôpital des Peupliers, Ramsay Générale de Santé, 75013 Paris, France.
Francois Salachas
APHP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Centre référent SLA
Jesus Mora Pardina
Hospital Universitario San Rafael
Abdelilah Assialioui
L'Hospitalet de Llobregat
Ricardo Rojas-García
Hospital de la Santa Creu i Sant Pau de Barcelona
ORCiD: https://orcid.org/0000-0003-1411-5573
Patrick Dion
McGill University
Jay Ross
McGill University
ORCiD: https://orcid.org/0000-0002-8183-2524
Albert Ludolph
German Center for Neurodegenerative Diseases
Jochen Weishaupt
Division of Neurodegeneration, Department of Neurology, University Medicine Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
David Brenner
Division of Neurodegeneration, Department of Neurology, University Medicine Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Axel Freischmidt
Department of Neurology, Ulm University, Ulm, Germany.
Gilbert Bensimon
Département de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, UPMC Pharmacologie, AP-HP, Paris, France.
Alexis Brice
INSERM U679
Alexandra Durr
INSERM
Christine Payan
AP-HP
Safa Saker-Delye
Genethon
Nicholas Wood
University College London
ORCiD: https://orcid.org/0000-0002-9500-3348
Simon Topp
King's College London
ORCiD: https://orcid.org/0000-0002-5200-3284
Rosa Rademakers
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
Lukas Tittmann
Christian-Albrechts University Kiel and Biobank popgen
Wolfgang Lieb
Institute of Epidemiology and Biobank popgen, University of Kiel
Andre Franke
Christian-Albrechts-University of Kiel
ORCiD: https://orcid.org/0000-0003-1530-5811
Stephan Ripke
Massachusetts General Hospital
Alice Braun
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin 10117, Germany.
Julia Kraft
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin 10117, Germany.
ORCiD: https://orcid.org/0000-0001-7306-1179
David Whiteman
QIMR Berghofer Medical Research Institute
ORCiD: https://orcid.org/0000-0003-2563-9559
Catherine Olsen
QIMR Berghofer Medical Research Institute
ORCiD: https://orcid.org/0000-0003-4483-1888
André Uitterlinden
Erasmus MC
ORCiD: https://orcid.org/0000-0002-7276-3387
Albert Hofman
Erasmus MC University Medical Centre Rotterdam
Marcella Rietschel
University of Mannheim
ORCiD: https://orcid.org/0000-0002-5236-6149
Sven Cichon
University of Bonn
Markus Nöthen
University of Bonn
Philippe Amouyel
Institut Pasteur de Lille
ORCiD: https://orcid.org/0000-0001-9088-234X
Bryan Traynor
National Institute on Aging
Andrew Singleton
National Institute on Aging
Miguel Mitne Neto
Fleury Group
Ruben Cauchi
Center for Molecular Medicine and Biobanking & Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Malta.
Roel Ophoff
University of California Los Angeles, University Medical Center Utrecht
Martina Wiedau-Pazos
University of California Los Angeles
Catherine Lomen-Hoerth
University of California
Vivianna Van Deerlin
University of Pennsylvania
ORCiD: https://orcid.org/0000-0002-7400-9097
Julian Grosskreutz
University Hospital Jena
Annekathrin Rödiger
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Alexander Jörk
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Tabea Barthel
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Erik Theele
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Berjamin Ilse
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Beatrice Stubendorff
University Hospital Jena
Otto Witte
Hans Berger Department of Neurology, Jena University Hospital
Robert Steinbach
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
Christian Hübner
Jena University Hospital
Caroline Graff
Karolinska Institutet
Lev Brylev
Department of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Vera Fominykh
Department of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Vera Demeshonok
ALS-care center, "GAOORDI", Medical Clinic of the St. Petersburg, St. Petersburg, Russia.
Anastasia Ataulina
Department of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Boris Rogelj
Jožef Stefan Institute
ORCiD: https://orcid.org/0000-0003-3898-1943
Blaž Koritnik
Ljubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, SI-1000 Ljubljana
ORCiD: https://orcid.org/0000-0002-5083-8261
Janez Zidar
University Clinical Center Ljubljana
Metka Ravnik-Glavač
University of Ljubljana
Damjan Glavač
Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Zorica Stević
Clinic of Neurology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia
Vivian Drory
Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel.
Mónica Povedano
L'Hospitalet de Llobregat
Ian Blair
Macquarie University
Matthew Kiernan
University of Syndey
Beben Benyamin
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Robert Henderson
Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4029, Australia.
Sarah Furlong
Centre for Motor Neuron Disease Research, Macquarie University, NSW 2109, Australia.
Susan Mathers
Calvary Health Care Bethlehem, Parkdale, VIC 3195, Australia.
Pamela McCombe
Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4019, Australia.
Merrilee Needham
Fiona Stanley Hospital, Perth, WA 6150, Australia.
Shyuan Ngo
The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia.
Garth Nicholson
Macquarie University
Roger Pamphlett
The University of Sydney
ORCiD: https://orcid.org/0000-0003-3326-7273
Dominic Rowe
Centre for Motor Neuron Disease Research, Macquarie University, New South Wales 2109, Australia
ORCiD: https://orcid.org/0000-0003-0912-2146
Frederik Steyn
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Kelly Williams
Macquarie University
ORCiD: https://orcid.org/0000-0001-6319-9473
Karen Mather
Centre for Healthy Brain Ageing, Psychiatry, University of New South Wales (UNSW)
ORCiD: https://orcid.org/0000-0003-4143-8941
Perminder Sachdev
ORCiD: https://orcid.org/0000-0002-9595-3220
Anjali Henders
University of Queensland
Leanne Wallace
University of Queensland
Mamede de Carvalho
Instituto de Medicina Molecular and Institute of Physiology, Faculty of Medicine, University of Lisbon, Portugal
Susana Pinto
Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Susanne Petri
Otto-von-Guericke University Magdeburg
Markus Weber
Kantonspital St. Gallen
Guy Rouleau
Department of Human Genetics, McGill University, Montréal, QC, Canada; Montreal Neurological Institute and Hospital, McGill University, Montréal, QC
ORCiD: https://orcid.org/0000-0001-8403-1418
Vincenzo Silani
IRCCS Istituto Auxologico Italiano-University of Milan Medical School
ORCiD: https://orcid.org/0000-0002-7698-3854
Charles Curtis
King's College London
Gerome Breen
King's College London
ORCiD: https://orcid.org/0000-0003-2053-1792
Jonathan Glass
Emory University
ORCiD: https://orcid.org/0000-0002-3295-4971
Robert Brown
University of Massachusetts Medical School
John Landers
University of Massachusetts Medical School
Christopher Shaw
Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London
Peter Andersen
Umeå University
ORCiD: https://orcid.org/0000-0003-0094-5429
Ewout Groen
University Medical Center Utrecht
ORCiD: https://orcid.org/0000-0002-2330-9444
Michael van Es
University Medical Center Utrecht
ORCiD: https://orcid.org/0000-0002-7709-5883
Jeroen Pasterkamp
University Medical Center Utrecht
ORCiD: https://orcid.org/0000-0003-1631-6440
Dongsheng Fan
Peking University Third Hospital
Fleur Garton
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Allan McRae
University of Queensland
George Davey Smith
University of Bristol
ORCiD: https://orcid.org/0000-0002-1407-8314
Tom Gaunt
University of Bristol
ORCiD: https://orcid.org/0000-0003-0924-3247
Michael Eberle
Illumina Inc.
ORCiD: https://orcid.org/0000-0001-8965-1253
Jonathan Mill
University of Exeter
ORCiD: https://orcid.org/0000-0003-1115-3224
Russell McLaughlin
Trinity College Dublin
ORCiD: https://orcid.org/0000-0003-3915-2135
Orla Hardiman
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D02 PN40, Ireland.
Kevin Kenna
University Medical Center Utrecht
Naomi Wray
University of Queensland
ORCiD: https://orcid.org/0000-0001-7421-3357
Ellen Tsai
Biogen
ORCiD: https://orcid.org/0000-0002-5625-1189
Heiko Runz
Translational Genome Sciences, Biogen, 225 Binney Street, Cambridge, MA 02142, USA
Lude Franke
University Medical Center Groningen
ORCiD: https://orcid.org/0000-0002-5159-8802
Ammar Al-Chalabi
King's College London
ORCiD: https://orcid.org/0000-0002-4924-7712
Philip Van Damme
Universitaire Ziekenhuizen Leuven
ORCiD: https://orcid.org/0000-0002-4010-2357
Nayana Gaur
Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
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