Evidence map›Paper›PMID 34873335›Full record

SynthesisNature genetics2021

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Wouter van Rheenen, Rick A A van der Spek, Mark K Bakker, Joke J F A van Vugt, Paul J Hop, Ramona A J Zwamborn, Niek de Klein, Harm-Jan Westra, Olivier B Bakker, Patrick Deelen and 186 more

Erratum issued Registry-linked trialOpen access · hybridAbstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in Nature genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT05892822 (Amyotrophic Lateral Sclerosis Registry), which is not on this map. Cited by 332 papers, 10 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
332citing papers in PubMed, 10 pooled it
40.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT05892822 unknown statusnot on this mapstarted 2023, after this paper: background citation

Amyotrophic Lateral Sclerosis Registry

Typeobservational_patient_registrySponsoryilong WangRan2023 to 2024Enrolled1,000ConditionsAmyotrophic Lateral SclerosisArmsAmyotrophic Lateral Sclerosis
3 · Its place in the literature

Who cites it

332 citing papers in PubMed, 10 syntheses or guidelines pooled it, 522 citations in OpenAlex.

  1. Pooled it
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  4. A systematic review and functionalFrontiers in neuroscience · 2025
    Pooled it
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  11. Article
  12. TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD.bioRxiv : the preprint server for biology · 2026
    Article
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  16. Shared genetic architecture between DTI-ALPS traits and neurodegenerative diseases.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
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272 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

196 authors at 20 institutions in 22 countries.

Wouter van Rheenen *Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. w.vanrheenen-2@umcutrecht.nl.ORCID http://orcid.org/0000-0002-5860-1533
Rick A A van der Spek *Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Mark K Bakker *Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0002-7887-9014
Joke J F A van VugtDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Paul J HopDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Ramona A J ZwambornDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Niek de KleinDepartment of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.ORCID http://orcid.org/0000-0003-4640-9904
Harm-Jan WestraDepartment of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.ORCID http://orcid.org/0000-0001-7038-567X
Olivier B BakkerDepartment of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
Patrick DeelenDepartment of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.ORCID http://orcid.org/0000-0002-5654-3966
Gemma ShirebyUniversity of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.
Eilis HannonUniversity of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.ORCID http://orcid.org/0000-0001-6840-072X
Matthieu MoisseDepartment of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, Leuven, Belgium.
Denis BairdTranslational Biology, Biogen, Boston, MA, USA.
Restuadi RestuadiInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Egor DolzhenkoIllumina, San Diego, CA, USA.
Annelot M DekkerDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Klara GaworDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0001-7571-5420
Henk-Jan WestenengDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Gijs H P TazelaarDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Kristel R van EijkDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Maarten KooymanDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0002-9023-5617
Ross P ByrneComplex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.ORCID http://orcid.org/0000-0002-4082-6072
Mark DohertyComplex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
Mark HeverinAcademic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Ahmad Al KhleifatMaurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.ORCID http://orcid.org/0000-0002-7406-9831
Alfredo IacoangeliMaurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Aleksey ShatunovMaurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Nicola TicozziDepartment of Neurology, Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milan, Italy.ORCID http://orcid.org/0000-0001-5963-7426
Johnathan Cooper-KnockSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Bradley N SmithMaurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Marta GromichoInstituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.ORCID http://orcid.org/0000-0003-2111-4579
Siddharthan ChandranEuan MacDonald Centre for Motor Neurone Disease Research, Edinburgh, UK.
Suvankar PalEuan MacDonald Centre for Motor Neurone Disease Research, Edinburgh, UK.
Karen E MorrisonSchool of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.ORCID http://orcid.org/0000-0003-0216-5717
Pamela J ShawSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
John HardyDepartment of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
Richard W OrrellDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
Michael SendtnerInstitute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.
Thomas MeyerCharité University Hospital, Humboldt University, Berlin, Germany.ORCID http://orcid.org/0000-0002-2736-7350
Nazli BaşakKoç University, School of Medicine, KUTTAM-NDAL, Istanbul, Turkey.
Anneke J van der KooiDepartment of Neurology, Academic Medical Center, Amsterdam, the Netherlands.
Antonia RattiDepartment of Neurology, Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milan, Italy.
Isabella FoghMaurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Cinzia GelleraUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
Giuseppe Lauria3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', MIlan, Italy.
Stefania CortiDepartment of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
Cristina CeredaGenomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.ORCID http://orcid.org/0000-0001-9571-0862
Daisy SprovieroGenomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.
Sandra D'AlfonsoDepartment of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Gianni SorarùDepartment of Neurosciences, University of Padova, Padova, Italy.
Gabriele SicilianoDepartment of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Massimiliano FilostoDepartment of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Alessandro PadovaniDepartment of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Adriano Chiò'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Andrea Calvo'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.ORCID http://orcid.org/0000-0002-5122-7243
Cristina Moglia'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Maura Brunetti'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Antonio Canosa'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.ORCID http://orcid.org/0000-0001-5876-4079
Maurizio Grassano'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Ettore BeghiLaboratory of Neurological Diseases, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Elisabetta PupilloLaboratory of Neurological Diseases, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Giancarlo LogroscinoDepartment of Clinical Research in Neurology, University of Bari at 'Pia Fondazione Card G. Panico' Hospital, Bari, Italy.
Beatrice NefussyNeuromuscular Diseases Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Alma OsmanovicDepartment of Neurology, Hannover Medical School, Hannover, Germany.
Angelica NordinDepartment of Clinical Sciences, Neurosciences, Umeå University, Umeå, Sweden.ORCID http://orcid.org/0000-0002-7703-647X
Yossef LernerFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Michal ZabariFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Marc GotkineFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.ORCID http://orcid.org/0000-0003-2541-6232
Robert H BalohCenter for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Shaughn BellCenter for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Patrick Vourc'hService de Biochimie et Biologie Moléculaire, CHU de Tours, Tours, France.
Philippe CorciaUMR 1253, Université de Tours, Inserm, Tours, France.
Philippe CouratierCentre de référence sur la SLA, CHRU de Limoges, Limoges, France.
Stéphanie MillecampsICM, Institut du Cerveau, Inserm, CNRS, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Vincent MeiningerHôpital des Peupliers, Ramsay Générale de Santé, Paris, France.
François SalachasICM, Institut du Cerveau, Inserm, CNRS, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Jesus S Mora PardinaALS Unit, Hospital San Rafael, Madrid, Spain.
Abdelilah AssialiouiFunctional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain.
Ricardo Rojas-GarcíaMND Clinic, Neurology Department, Hospital de la Santa Creu i Sant Pau de Barcelona, Universitat Autonoma de Barcelona, Barcelona, Spain.ORCID http://orcid.org/0000-0003-1411-5573
Patrick A DionMontreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
Jay P RossMontreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.ORCID http://orcid.org/0000-0002-8183-2524
Albert C LudolphDepartment of Neurology, Ulm University, Ulm, Germany.
Jochen H WeishauptDivision of Neurodegeneration, Department of Neurology, University Medicine Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
David BrennerDivision of Neurodegeneration, Department of Neurology, University Medicine Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Axel FreischmidtDepartment of Neurology, Ulm University, Ulm, Germany.
Gilbert BensimonDépartement de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, UPMC Pharmacologie, AP-HP, Paris, France.
Alexis BriceSorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France.
Alexandra DurrSorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France.
Christine A M PayanDépartement de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, UPMC Pharmacologie, AP-HP, Paris, France.
Safa Saker-DelyeGenethon, CNRS UMR, Evry, France.
Nicholas W WoodDepartment of Clinical and Movement Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.ORCID http://orcid.org/0000-0002-9500-3348
Simon ToppMaurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.ORCID http://orcid.org/0000-0002-5200-3284
Rosa RademakersDepartment of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
Lukas TittmannPopgen Biobank and Institute of Epidemiology, Christian Albrechts-University Kiel, Kiel, Germany.
Wolfgang LiebPopgen Biobank and Institute of Epidemiology, Christian Albrechts-University Kiel, Kiel, Germany.ORCID http://orcid.org/0000-0003-2544-4460
Andre FrankeInstitute of Clinical Molecular Biology, Kiel University, Kiel, Germany.ORCID http://orcid.org/0000-0003-1530-5811
Stephan RipkeAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Alice BraunDepartment of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.ORCID http://orcid.org/0000-0003-1145-0261
Julia KraftDepartment of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.ORCID http://orcid.org/0000-0001-7306-1179
David C WhitemanCancer Control Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.ORCID http://orcid.org/0000-0003-2563-9559
Catherine M OlsenCancer Control Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.ORCID http://orcid.org/0000-0003-4483-1888
Andre G UitterlindenDepartment of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.ORCID http://orcid.org/0000-0002-7276-3387
Albert HofmanDepartment of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
Marcella RietschelMedical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.ORCID http://orcid.org/0000-0002-5236-6149
Sven CichonInstitute of Human Genetics, University of Bonn, Bonn, Germany.
Markus M NöthenInstitute of Human Genetics, University of Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0002-8770-2464
Philippe AmouyelINSERM UMR1167-RID-AGE LabEx DISTALZ-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille, Centre Hospitalier of the University of Lille, Institut Pasteur de Lille, Lille, France.ORCID http://orcid.org/0000-0001-9088-234X
SLALOM Consortium
PARALS Consortium
SLAGEN Consortium
SLAP Consortium
Bryan J TraynorNeuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, USA.
Andrew B SingletonMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, USA.
Miguel Mitne NetoUniversidade de São Paulo, São Paulo, Brazil.
Ruben J CauchiCentre for Molecular Medicine and Biobanking and Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.ORCID http://orcid.org/0000-0001-6150-1608
Roel A OphoffUniversity Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, the Netherlands.
Martina Wiedau-PazosDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Catherine Lomen-HoerthDepartment of Neurology, University of California, San Francisco, CA, USA.
Vivianna M van DeerlinCenter for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-7400-9097
Julian GrosskreutzHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.ORCID http://orcid.org/0000-0001-9525-1424
Annekathrin RoedigerHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Nayana GaurHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Alexander JörkHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Tabea BarthelHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Erik TheeleHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Benjamin IlseHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Beatrice StubendorffHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Otto W WitteHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Robert SteinbachHans Berger Department of Neurology, Jena University Hospital, Jena, Germany.ORCID http://orcid.org/0000-0003-3936-6010
Christian A HübnerInstitute of Human Genetics, Jena University Hospital, Jena, Germany.
Caroline GraffDepartment of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Lev BrylevDepartment of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Vera FominykhDepartment of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.ORCID http://orcid.org/0000-0001-5490-2390
Vera DemeshonokALS-Care Center, 'GAOORDI', Medical Clinic of the St. Petersburg, St. Petersburg, Russia.
Anastasia AtaulinaDepartment of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Boris RogeljDepartment of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.ORCID http://orcid.org/0000-0003-3898-1943
Blaž KoritnikLjubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.ORCID http://orcid.org/0000-0002-5083-8261
Janez ZidarLjubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Metka Ravnik-GlavačInstitute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Damjan GlavačDepartment of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Zorica StevićClinic of Neurology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
Vivian DroryNeuromuscular Diseases Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Monica PovedanoFunctional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain.
Ian P BlairCentre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
Matthew C KiernanBrain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
Beben BenyaminInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Robert D HendersonCentre for Clinical Research, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia.
Sarah FurlongCentre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
Susan MathersCalvary Health Care Bethlehem, Parkdale, Victoria, Australia.ORCID http://orcid.org/0000-0001-8445-1594
Pamela A McCombeDepartment of Neurology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Merrilee NeedhamFiona Stanley Hospital, Perth, Western Australia, Australia.
Shyuan T NgoCentre for Clinical Research, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia.ORCID http://orcid.org/0000-0002-1388-2108
Garth A NicholsonCentre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
Roger PamphlettDiscipline of Pathology and Department of Neuropathology, Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0003-3326-7273
Dominic B RoweCentre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0003-0912-2146
Frederik J SteynDepartment of Neurology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Kelly L WilliamsCentre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0001-6319-9473
Karen A MatherCentre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0003-4143-8941
Perminder S SachdevCentre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-9595-3220
Anjali K HendersInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Leanne WallaceInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Mamede de CarvalhoInstituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Susana PintoInstituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Susanne PetriDepartment of Neurology, Hannover Medical School, Hannover, Germany.
Markus WeberNeuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Guy A RouleauMontreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.ORCID http://orcid.org/0000-0001-8403-1418
Vincenzo SilaniDepartment of Neurology, Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milan, Italy.ORCID http://orcid.org/0000-0002-7698-3854
Charles J CurtisSocial Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
Gerome BreenSocial Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.ORCID http://orcid.org/0000-0003-2053-1792
Jonathan D GlassDepartment Neurology, Emory University School of Medicine, Atlanta, GA, USA.ORCID http://orcid.org/0000-0002-3295-4971
Robert H BrownDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.ORCID http://orcid.org/0000-0001-6062-1528
John E LandersDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.ORCID http://orcid.org/0000-0001-8084-5043
Christopher E ShawMaurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Peter M AndersenDepartment of Clinical Sciences, Neurosciences, Umeå University, Umeå, Sweden.ORCID http://orcid.org/0000-0003-0094-5429
Ewout J N GroenDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0002-2330-9444
Michael A van EsDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0002-7709-5883
R Jeroen PasterkampDepartment of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0003-1631-6440
Dongsheng FanDepartment of Neurology, Third Hospital, Peking University, Beijing, China.
Fleur C GartonInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Allan F McRaeInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
George Davey SmithMRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, UK.ORCID http://orcid.org/0000-0002-1407-8314
Tom R GauntMRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, UK.ORCID http://orcid.org/0000-0003-0924-3247
Michael A EberleIllumina, San Diego, CA, USA.ORCID http://orcid.org/0000-0001-8965-1253
Jonathan MillUniversity of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.ORCID http://orcid.org/0000-0003-1115-3224
Russell L McLaughlinComplex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.ORCID http://orcid.org/0000-0003-3915-2135
Orla HardimanAcademic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Kevin P KennaDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Naomi R WrayInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.ORCID http://orcid.org/0000-0001-7421-3357
Ellen TsaiTranslational Biology, Biogen, Boston, MA, USA.ORCID http://orcid.org/0000-0002-5625-1189
Heiko RunzTranslational Biology, Biogen, Boston, MA, USA.
Lude FrankeDepartment of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.ORCID http://orcid.org/0000-0002-5159-8802
Ammar Al-ChalabiMaurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.ORCID http://orcid.org/0000-0002-4924-7712
Philip Van DammeDepartment of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, Leuven, Belgium.ORCID http://orcid.org/0000-0002-4010-2357
Leonard H van den BergDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Jan H VeldinkDepartment of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. j.h.veldink@umcutrecht.nl.ORCID http://orcid.org/0000-0001-5572-9657
Utrecht University · NLUniversity of Turin · ITThe University of Queensland · AUAzienda Ospedaliera Citta' della Salute e della Scienza di Torino · ITJena University Hospital · DEKing's College London · GBUniversità degli Studi del Piemonte Orientale “Amedeo Avogadro” · ITCentre National de la Recherche Scientifique · FRTrinity College Dublin · IEUniversity Medical Center Groningen · NLUniversity of Milan · ITFondazione IRCCS Istituto Neurologico Carlo Besta · ITMacquarie University · AUBiogen (United States) · USCenter for Genomic Science · ITChristian-Albrechts-Universität zu Kiel · DEFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico · ITFondazione Istituto Neurologico Nazionale Casimiro Mondino · ITHebrew University of Jerusalem · ILHeidelberg University · DE

Funding

Testing Hypotheses by Site Directed Mutagenesis of SOD1P01NS049134 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI WIEDAU-PAZOS, MARTINA H · 2005 to 2014
$10.9M
Identification of genes causative for familial ALS gene using exome sequencingR01NS073873 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI LANDERS, JOHN E · 2011 to 2019
$4.6M
Gsk-3beta &beta-Catenin in pathophysiology of FTDP-17K08NS002240 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI WIEDAU-PAZOS, MARTINA H · 2004 to 2008
$887k
Identification and Characterization of ALS/FTD Associated Variants Using Whole Genome SequencingR56NS073873 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI LANDERS, JOHN E · 2020 to 2020
$586k
Medical Research Council G0500289Medical Research Council G0600974Medical Research Council G0701075Medical Research Council G0900635Medical Research Council G0900688Medical Research Council G0901254Medical Research Council G1001253Medical Research Council G1100695Medical Research Council MC_G1000733Medical Research Council MC_PC_17115Medical Research Council MC_UU_00011/1Medical Research Council MC_UU_00011/4Medical Research Council MR/J004758/1Medical Research Council MR/K01417X/1Medical Research Council MR/L021803/1Medical Research Council MR/L023784/2Medical Research Council MR/L501529/1Medical Research Council MR/L501542/1Medical Research Council MR/R024804/1Motor Neurone Disease Association ALCHALABI-DOBSON/APR14/829-791Motor Neurone Disease Association ALCHALABI-TALBOT/APR14/926-794Motor Neurone Disease Association SHAW/APR15/970-797Motor Neurone Disease Association SHAW/NOV14/985-797Motor Neurone Disease Association SMITH/APR16/847-791MRF_ MRF-060-0003-RG-SMITHNINDS NIH HHS K08 NS002240NINDS NIH HHS P01 NS049134NINDS NIH HHS R01 NS073873NINDS NIH HHS R56 NS073873Parkinson's UK G-0907Parkinson's UK G-1307
6 · The paper itself

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats 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 lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

Indexed as

Genome-Wide Association StudyMutationAmyotrophic Lateral SclerosisBrainCholesterolDisease ProgressionFemaleGlutamineHumansMaleMendelian Randomization AnalysisMicrosatellite RepeatsNeurodegenerative DiseasesNeuronsQuantitative Trait LociRisk FactorsCholesterolGlutamine

Identifiers

PMID34873335
PMCPMC8648564
OpenAlexW4226286160

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Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.