2. Academic Validation
  3. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

  • Nat Genet. 2016 Sep;48(9):1037-42. doi: 10.1038/ng.3626.
Kevin P Kenna 1,  Perry T C van Doormaal 2,  Annelot M Dekker 2,  Nicola Ticozzi 3 4,  Brendan J Kenna 1,  Frank P Diekstra 2,  Wouter van Rheenen 2,  Kristel R van Eijk 2,  Ashley R Jones 5,  Pamela Keagle 1,  Aleksey Shatunov 5,  William Sproviero 5,  Bradley N Smith 5,  Michael A van Es 2,  Simon D Topp 5,  Aoife Kenna 1,  Jack W Miller 5,  Claudia Fallini 1,  Cinzia Tiloca 3 6,  Russell L McLaughlin 7,  Caroline Vance 5,  Claire Troakes 5,  Claudia Colombrita 3 4,  Gabriele Mora 8,  Andrea Calvo 9,  Federico Verde 3 4,  Safa Al-Sarraj 5,  Andrew King 5,  Daniela Calini 3,  Jacqueline de Belleroche 10,  Frank Baas 11,  Anneke J van der Kooi 12,  Marianne de Visser 12,  Anneloor L M A Ten Asbroek 11,  Peter C Sapp 1,  Diane McKenna-Yasek 1,  Meraida Polak 13,  Seneshaw Asress 13,  José Luis Muñoz-Blanco 14,  Tim M Strom 15,  Thomas Meitinger 16,  Karen E Morrison 17,  SLAGEN Consortium,  Giuseppe Lauria 18,  Kelly L Williams 19,  P Nigel Leigh 20,  Garth A Nicholson 19 21,  Ian P Blair 19,  Claire S Leblond 22,  Patrick A Dion 22,  Guy A Rouleau 22,  Hardev Pall 23 24,  Pamela J Shaw 25,  Martin R Turner 25,  Kevin Talbot 25,  Franco Taroni 26,  Kevin B Boylan 27,  Marka Van Blitterswijk 28,  Rosa Rademakers 28,  Jesús Esteban-Pérez 29 30,  Alberto García-Redondo 29 30,  Phillip Van Damme 31 32,  Wim Robberecht 31 32,  Adriano Chio 9,  Cinzia Gellera 26,  Carsten Drepper 33 34,  Michael Sendtner 33,  Antonia Ratti 3 4,  Jonathan D Glass 13,  Jesús S Mora 35,  Nazli A Basak 36,  Orla Hardiman 7,  Albert C Ludolph 37,  Peter M Andersen 38,  Jochen H Weishaupt 37,  Robert H Brown Jr 1,  Ammar Al-Chalabi 5,  Vincenzo Silani 3 4,  Christopher E Shaw 5,  Leonard H van den Berg 2,  Jan H Veldink 2,  John E Landers 1
Affiliations

Affiliations

  • 1 Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • 2 Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • 3 Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.
  • 4 Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
  • 5 Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • 6 Doctoral School in Molecular Medicine, Department of Sciences and Biomedical Technologies, Università degli Studi di Milano, Milan, Italy.
  • 7 Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
  • 8 Salvatore Maugeri Foundation, IRCSS, Scientific Institute of Milano, Milan, Italy.
  • 9 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
  • 10 Neurogenetics Group, Division of Brain Sciences, Imperial College London, London, UK.
  • 11 Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
  • 12 Department of Neurogenetics and Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
  • 13 Department of Neurology, Emory University, Atlanta, Georgia, USA.
  • 14 Unidad de ELA, Instituto de Investigación Hospital Gregorio Marañón de Madrid, Madrid, Spain.
  • 15 Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
  • 16 Institute of Human Genetics, Technische Universität München, Munich, Germany.
  • 17 Faculty of Medicine, University of Southampton, Southampton, UK.
  • 18 3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
  • 19 Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
  • 20 Trafford Centre for Medical Research, Brighton and Sussex Medical School, Falmer, UK.
  • 21 ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia.
  • 22 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
  • 23 Institute of Clinical Studies, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
  • 24 Department of Neurology, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, UK.
  • 25 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
  • 26 Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
  • 27 Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
  • 28 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • 29 Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Madrid, Spain.
  • 30 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) U-723, Madrid, Spain.
  • 31 Laboratory of Neurobiology, Department of Neurosciences, KU Leuven and Vesalius Research Centre, VIB, Leuven, Belgium.
  • 32 Department of Neurology, University Hospitals, Leuven, Belgium.
  • 33 Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.
  • 34 Department of Child and Adolescent Psychiatry, University Hospital of Würzburg, Würzburg, Germany.
  • 35 ALS Unit/Neurology, Hospital San Rafael, Madrid, Spain.
  • 36 NDAL, Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.
  • 37 Neurology Department, Ulm University, Ulm, Germany.
  • 38 Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
PMID: 27455347 DOI: 10.1038/ng.3626
Abstract

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

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