title: NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.
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.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Kenna
authors.affiliation: Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Perry T C
authors.initials: PT
authors.lastname: van Doormaal
authors.affiliation: Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Annelot M
authors.initials: AM
authors.lastname: Dekker
authors.affiliation: Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.|Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ticozzi
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Kenna
authors.affiliation: Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Diekstra
authors.affiliation: Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: van Rheenen
authors.affiliation: Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Kristel R
authors.initials: KR
authors.lastname: van Eijk
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Jones
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Keagle
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Shatunov
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: William
authors.identifier: 0000-0002-9335-9260
authors.initials: W
authors.lastname: Sproviero
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.affiliation: Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Simon D
authors.identifier: 0000-0002-5200-3284
authors.initials: SD
authors.lastname: Topp
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Aoife
authors.initials: A
authors.lastname: Kenna
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Miller
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fallini
authors.affiliation: Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.|Doctoral School in Molecular Medicine, Department of Sciences and Biomedical Technologies, Università degli Studi di Milano, Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Tiloca
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Russell L
authors.initials: RL
authors.lastname: McLaughlin
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.|Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Colombrita
authors.affiliation: Salvatore Maugeri Foundation, IRCSS, Scientific Institute of Milano, Milan, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mora
authors.affiliation: 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
authors.forename: Andrea
authors.identifier: 0000-0002-5122-7243
authors.initials: A
authors.lastname: Calvo
authors.affiliation: Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.|Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Verde
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.affiliation: Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Calini
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Belleroche
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Frank
authors.identifier: 0000-0003-3912-5428
authors.initials: F
authors.lastname: Baas
authors.affiliation: Department of Neurogenetics and Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anneke J
authors.initials: AJ
authors.lastname: van der Kooi
authors.affiliation: Department of Neurogenetics and Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: de Visser
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anneloor L M A
authors.initials: AL
authors.lastname: Ten Asbroek
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Sapp
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: McKenna-Yasek
authors.affiliation: Department of Neurology, Emory University, Atlanta, Georgia, USA.
authors.forename: Meraida
authors.initials: M
authors.lastname: Polak
authors.affiliation: Department of Neurology, Emory University, Atlanta, Georgia, USA.
authors.forename: Seneshaw
authors.initials: S
authors.lastname: Asress
authors.affiliation: Unidad de ELA, Instituto de Investigación Hospital Gregorio Marañón de Madrid, Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Muñoz-Blanco
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.affiliation: 3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria
authors.affiliation: Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
authors.forename: Kelly L
authors.identifier: 0000-0001-6319-9473
authors.initials: KL
authors.lastname: Williams
authors.affiliation: Trafford Centre for Medical Research, Brighton and Sussex Medical School, Falmer, UK.
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.affiliation: Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.|ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Blair
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leblond
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Institute of Clinical Studies, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.|Department of Neurology, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Hardev
authors.initials: H
authors.lastname: Pall
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Martin R
authors.identifier: 0000-0003-0267-3180
authors.initials: MR
authors.lastname: Turner
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Kevin
authors.identifier: 0000-0001-5490-1697
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Franco
authors.identifier: 0000-0002-2420-5233
authors.initials: F
authors.lastname: Taroni
authors.affiliation: Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Marka
authors.initials: M
authors.lastname: Van Blitterswijk
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) U-723, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Esteban-Pérez
authors.affiliation: Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) U-723, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: García-Redondo
authors.affiliation: Laboratory of Neurobiology, Department of Neurosciences, KU Leuven and Vesalius Research Centre, VIB, Leuven, Belgium.|Department of Neurology, University Hospitals, Leuven, Belgium.
authors.forename: Phillip
authors.initials: P
authors.lastname: Van Damme
authors.affiliation: Laboratory of Neurobiology, Department of Neurosciences, KU Leuven and Vesalius Research Centre, VIB, Leuven, Belgium.|Department of Neurology, University Hospitals, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.affiliation: 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chio
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Gellera
authors.affiliation: Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.|Department of Child and Adolescent Psychiatry, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Carsten
authors.identifier: 0000-0002-7883-6479
authors.initials: C
authors.lastname: Drepper
authors.affiliation: Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
authors.affiliation: Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.|Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Ratti
authors.affiliation: Department of Neurology, Emory University, Atlanta, Georgia, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
authors.affiliation: ALS Unit/Neurology, Hospital San Rafael, Madrid, Spain.
authors.forename: Jesús S
authors.initials: JS
authors.lastname: Mora
authors.affiliation: NDAL, Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.
authors.forename: Nazli A
authors.initials: NA
authors.lastname: Basak
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.affiliation: Neurology Department, Ulm University, Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.affiliation: Neurology Department, Ulm University, Ulm, Germany.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.affiliation: Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.|Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.affiliation: Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D059472:Exome / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*; D000072380:NIMA-Related Kinase 1 / Q000235:genetics*; D009426:Netherlands / Q000453:epidemiology
chemical_list: C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1