Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

doi:10.1038/ng.3622

Comparative Study

. 2016 Sep;48(9):1043-8.

doi: 10.1038/ng.3622. Epub 2016 Jul 25.

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Wouter van Rheenen¹, Aleksey Shatunov², Annelot M Dekker¹, Russell L McLaughlin³, Frank P Diekstra¹, Sara L Pulit⁴, Rick A A van der Spek¹, Urmo Võsa⁵, Simone de Jong^{6

7}, Matthew R Robinson⁸, Jian Yang⁸, Isabella Fogh^{2

9}, Perry Tc van Doormaal¹, Gijs H P Tazelaar¹, Max Koppers^{1

10}, Anna M Blokhuis^{1

10}, William Sproviero², Ashley R Jones², Kevin P Kenna¹¹, Kristel R van Eijk¹, Oliver Harschnitz^{1

10}, Raymond D Schellevis¹, William J Brands¹, Jelena Medic¹, Androniki Menelaou⁴, Alice Vajda^{12

13}, Nicola Ticozzi^{9

14}, Kuang Lin², Boris Rogelj^{15

16}, Katarina Vrabec¹⁷, Metka Ravnik-Glavač^{17

18}, Blaž Koritnik¹⁹, Janez Zidar¹⁹, Lea Leonardis¹⁹, Leja Dolenc Grošelj¹⁹, Stéphanie Millecamps²⁰, François Salachas^{20

21

22}, Vincent Meininger^{23

24}, Mamede de Carvalho^{25

26}, Susana Pinto^{25

26}, Jesus S Mora²⁷, Ricardo Rojas-García^{28

29}, Meraida Polak^{30

31}, Siddharthan Chandran^{32

33}, Shuna Colville³², Robert Swingler³², Karen E Morrison³⁴, Pamela J Shaw³⁵, John Hardy³⁶, Richard W Orrell³⁷, Alan Pittman^{36

38}, Katie Sidle³⁷, Pietro Fratta³⁹, Andrea Malaspina^{40

41}, Simon Topp², Susanne Petri⁴², Susanne Abdulla⁴³, Carsten Drepper⁴⁴, Michael Sendtner⁴⁴, Thomas Meyer⁴⁵, Roel A Ophoff^{46

47

48}, Kim A Staats⁴⁸, Martina Wiedau-Pazos⁴⁹, Catherine Lomen-Hoerth⁵⁰, Vivianna M Van Deerlin⁵¹, John Q Trojanowski⁵¹, Lauren Elman⁵², Leo McCluskey⁵², A Nazli Basak⁵³, Ceren Tunca⁵³, Hamid Hamzeiy⁵³, Yesim Parman⁵⁴, Thomas Meitinger⁵⁵, Peter Lichtner⁵⁵, Milena Radivojkov-Blagojevic⁵⁵, Christian R Andres⁵⁶, Cindy Maurel⁵⁶, Gilbert Bensimon^{57

58

59}, Bernhard Landwehrmeyer⁶⁰, Alexis Brice^{61

62

63

64

65}, Christine A M Payan^{57

59}, Safaa Saker-Delye⁶⁶, Alexandra Dürr⁶⁷, Nicholas W Wood⁶⁸, Lukas Tittmann⁶⁹, Wolfgang Lieb⁶⁹, Andre Franke⁷⁰, Marcella Rietschel⁷¹, Sven Cichon^{72

73

74

75

76}, Markus M Nöthen^{72

73}, Philippe Amouyel⁷⁷, Christophe Tzourio⁷⁸, Jean-François Dartigues⁷⁸, Andre G Uitterlinden^{79

80}, Fernando Rivadeneira^{79

80}, Karol Estrada⁷⁹, Albert Hofman^{80

81}, Charles Curtis^{6

7}, Hylke M Blauw¹, Anneke J van der Kooi⁸², Marianne de Visser⁸², An Goris⁸³, Markus Weber⁸⁴, Christopher E Shaw², Bradley N Smith², Orietta Pansarasa⁸⁵, Cristina Cereda⁸⁵, Roberto Del Bo⁸⁶, Giacomo P Comi⁸⁶, Sandra D'Alfonso⁸⁷, Cinzia Bertolin⁸⁸, Gianni Sorarù⁸⁸, Letizia Mazzini⁸⁹, Viviana Pensato⁹⁰, Cinzia Gellera⁹⁰, Cinzia Tiloca⁹, Antonia Ratti^{9

14}, Andrea Calvo^{91

92}, Cristina Moglia^{91

92}, Maura Brunetti^{91

92}, Simona Arcuti⁹³, Rosa Capozzo⁹³, Chiara Zecca⁹³, Christian Lunetta⁹⁴, Silvana Penco⁹⁵, Nilo Riva⁹⁶, Alessandro Padovani⁹⁷, Massimiliano Filosto⁹⁷, Bernard Muller⁹⁸, Robbert Jan Stuit⁹⁸; PARALS Registry; SLALOM Group; SLAP Registry; FALS Sequencing Consortium; SLAGEN Consortium; NNIPPS Study Group; Ian Blair⁹⁹, Katharine Zhang⁹⁹, Emily P McCann⁹⁹, Jennifer A Fifita⁹⁹, Garth A Nicholson^{99

100}, Dominic B Rowe⁹⁹, Roger Pamphlett¹⁰¹, Matthew C Kiernan¹⁰², Julian Grosskreutz¹⁰³, Otto W Witte¹⁰³, Thomas Ringer¹⁰³, Tino Prell¹⁰³, Beatrice Stubendorff¹⁰³, Ingo Kurth¹⁰⁴, Christian A Hübner¹⁰⁴, P Nigel Leigh¹⁰⁵, Federico Casale⁹¹, Adriano Chio^{91

92}, Ettore Beghi¹⁰⁶, Elisabetta Pupillo¹⁰⁶, Rosanna Tortelli⁹³, Giancarlo Logroscino^{107

108}, John Powell², Albert C Ludolph⁶⁰, Jochen H Weishaupt⁶⁰, Wim Robberecht^{83

109

110}, Philip Van Damme^{83

109

110}, Lude Franke⁵, Tune H Pers^{111

112

113

114

115}, Robert H Brown¹¹, Jonathan D Glass^{30

31}, John E Landers¹¹, Orla Hardiman^{12

13}, Peter M Andersen^{60

116}, Philippe Corcia^{56

117

118}, Patrick Vourc'h⁵⁶, Vincenzo Silani^{9

14}, Naomi R Wray⁸, Peter M Visscher^{8

119}, Paul I W de Bakker^{4

120}, Michael A van Es¹, R Jeroen Pasterkamp¹⁰, Cathryn M Lewis^{6

121}, Gerome Breen^{6

7}, Ammar Al-Chalabi², Leonard H van den Berg¹, Jan H Veldink¹

Affiliations

¹ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
² Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London, UK.
³ Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
⁴ Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵ Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
⁶ MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁷ NIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
⁹ Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
¹⁰ Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
¹¹ Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
¹² Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Ireland.
¹³ Department of Neurology, Beaumont Hospital, Dublin, Ireland.
¹⁴ Department of Pathophysiology and Tranplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
¹⁵ Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
¹⁶ Biomedical Research Institute BRIS, Ljubljana, Slovenia.
¹⁷ Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
¹⁸ Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
¹⁹ Ljubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
²⁰ Institut du Cerveau et de la Moelle Epinière, INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Paris, France.
²¹ Centre de Référence Maladies Rares SLA Ile de France, Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France.
²² GRC-UPMC SLA et Maladies du Motoneurone, Paris, France.
²³ Ramsay Generale de Santé, Hôpital Peupliers, Paris, France.
²⁴ Réseau SLA Ile de France, Paris, France.
²⁵ Institute of Physiology, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
²⁶ Department of Neurosciences, Hospital de Santa Maria-CHLN, Lisbon, Portugal.
²⁷ Department of Neurology, Hospital San Rafael, Madrid, Spain.
²⁸ Neurology Department, Hospital de la Santa Creu i Sant Pau de Barcelona, Autonomous University of Barcelona, Barcelona, Spain.
²⁹ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
³⁰ Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
³¹ Emory ALS Center, Emory University School of Medicine, Atlanta, Georgia, USA.
³² Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh, UK.
³³ Centre for Neuroregeneration and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
³⁴ Faculty of Medicine, University of Southampton, Southampton, UK.
³⁵ Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
³⁶ Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
³⁷ Department of Clinical Neuroscience, Institute of Neurology, University College London, London, UK.
³⁸ Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK.
³⁹ Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK.
⁴⁰ Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London, UK.
⁴¹ North-East London and Essex Regional Motor Neuron Disease Care Centre, London, UK.
⁴² Department of Neurology, Hannover Medical School, Hannover, Germany.
⁴³ Department of Neurology, Otto von Güricke University Magdeburg, Magdeburg, Germany.
⁴⁴ Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.
⁴⁵ Department of Neurology, Charité University Hospital, Humboldt University, Berlin, Germany.
⁴⁶ Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
⁴⁷ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
⁴⁸ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
⁴⁹ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
⁵⁰ Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
⁵¹ Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵² Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵³ Neurodegeneration Research Laboratory, Bo[gcaron]aziçi University, Istanbul, Turkey.
⁵⁴ Neurology Department, Istanbul Medical School, Istanbul University, Istanbul, Turkey.
⁵⁵ Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
⁵⁶ INSERM U930, Université François Rabelais, Tours, France.
⁵⁷ AP-HP, Département de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁵⁸ UPMC, Pharmacologie, Paris VI, Paris, France.
⁵⁹ BESPIM, CHU de Nîmes, Nîmes, France.
⁶⁰ Department of Neurology, Ulm University, Ulm, Germany.
⁶¹ INSERM U1127, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶² CNRS UMR 7225, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶³ Sorbonne Universités, UPMC Paris 06, UMRS 1127, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶⁴ Institut du Cerveau et de la Moelle Epinière, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶⁵ AP-HP, Département de Génétique, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶⁶ Genethon, CNRS UMR 8587, Evry, France.
⁶⁷ Department of Medical Genetics, Institut du Cerveau et de la Moelle Epinière, Hôptial Pitié-Salpêtrière, Paris, France.
⁶⁸ Department of Neurogenetics, Institute of Neurology, University College London, London, UK.
⁶⁹ PopGen Biobank and Institute of Epidemiology, Christian Albrechts University Kiel, Kiel, Germany.
⁷⁰ Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
⁷¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Heidelberg, Germany.
⁷² Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁷³ Department of Genomics, Life and Brain Center, Bonn, Germany.
⁷⁴ Division of Medical Genetics, University Hospital Basel, University of Basel, Basel, Switzerland.
⁷⁵ Department of Biomedicine, University of Basel, Basel, Switzerland.
⁷⁶ Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Juelich, Germany.
⁷⁷ University of Lille, INSERM, CHU de Lille, Institut Pasteur de Lille, U1167-RID-AGE Risk Factor and Molecular Determinants of Aging Diseases, Lille, France.
⁷⁸ Bordeaux University, ISPED, Centre INSERM U1219-Epidemiologie Biostatistique et CIC-1401, CHU de Bordeaux, Pôle de Santé Publique, Bordeaux, France.
⁷⁹ Department of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
⁸⁰ Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
⁸¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁸² Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
⁸³ Department of Neurosciences, Experimental Neurology, Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, Belgium.
⁸⁴ Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.
⁸⁵ Laboratory of Experimental Neurobiology, IRCCS 'C. Mondino' National Institute of Neurology Foundation, Pavia, Italy.
⁸⁶ Neurologic Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁸⁷ Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, Università del Piemonte Orientale, Novara, Italy.
⁸⁸ Department of Neurosciences, University of Padova, Padova, Italy.
⁸⁹ Department of Neurology, Università del Piemonte Orientale, Novara, Italy.
⁹⁰ Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
⁹¹ 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
⁹² Azienda Ospedaliera Città della Salute e della Scienza, Turin, Italy.
⁹³ Department of Clinical Research in Neurology, University of Bari 'A. Moro' at Pia Fondazione 'Card. G. Panico', Tricase, Italy.
⁹⁴ NEMO Clinical Center, Serena Onlus Foundation, Niguarda Ca' Granda Hostipal, Milan, Italy.
⁹⁵ Medical Genetics Unit, Department of Laboratory Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.
⁹⁶ Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
⁹⁷ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁹⁸ Project MinE Foundation, Rotterdam, the Netherlands.
⁹⁹ Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
¹⁰⁰ University of Sydney, ANZAC Research Institute, Concord Hospital, Sydney, New South Wales, Australia.
¹⁰¹ Stacey MND Laboratory, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.
¹⁰² Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
¹⁰³ Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
¹⁰⁴ Institute of Human Genetics, Jena University Hospital, Jena, Germany.
¹⁰⁵ Department of Neurology, Brighton and Sussex Medical School Trafford Centre for Biomedical Research, University of Sussex, Falmer, UK.
¹⁰⁶ Laboratory of Neurological Diseases, Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
¹⁰⁷ Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
¹⁰⁸ Unit of Neurodegenerative Diseases, Department of Clinical Research in Neurology, University of Bari 'Aldo Moro' at Pia Fondazione Cardinale G. Panico, Tricase, Italy.
¹⁰⁹ Vesalius Research Center, Laboratory of Neurobiology, VIB, Leuven, Belgium.
¹¹⁰ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
¹¹¹ Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
¹¹² Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, USA.
¹¹³ Center for Basic Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.
¹¹⁴ Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
¹¹⁵ Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
¹¹⁶ Department of Pharmacology and Clinical Neurosience, Umeå University, Umeå, Sweden.
¹¹⁷ Centre SLA, CHRU de Tours, Tours, France.
¹¹⁸ Federation des Centres SLA Tours and Limoges, LITORALS, Tours, France.
¹¹⁹ Diamantina Institute, University of Queensland Translational Research Institute, Brisbane, Queensland, Australia.
¹²⁰ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
¹²¹ Department of Medical and Molecular Genetics, King's College London, London, UK.

PMID: 27455348
PMCID: PMC5556360
DOI: 10.1038/ng.3622

Comparative Study

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Wouter van Rheenen et al. Nat Genet. 2016 Sep.

. 2016 Sep;48(9):1043-8.

doi: 10.1038/ng.3622. Epub 2016 Jul 25.

Authors

Affiliations

¹ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
² Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London, UK.
³ Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
⁴ Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵ Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
⁶ MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁷ NIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
⁹ Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
¹⁰ Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
¹¹ Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
¹² Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Ireland.
¹³ Department of Neurology, Beaumont Hospital, Dublin, Ireland.
¹⁴ Department of Pathophysiology and Tranplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
¹⁵ Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
¹⁶ Biomedical Research Institute BRIS, Ljubljana, Slovenia.
¹⁷ Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
¹⁸ Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
¹⁹ Ljubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
²⁰ Institut du Cerveau et de la Moelle Epinière, INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Paris, France.
²¹ Centre de Référence Maladies Rares SLA Ile de France, Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France.
²² GRC-UPMC SLA et Maladies du Motoneurone, Paris, France.
²³ Ramsay Generale de Santé, Hôpital Peupliers, Paris, France.
²⁴ Réseau SLA Ile de France, Paris, France.
²⁵ Institute of Physiology, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
²⁶ Department of Neurosciences, Hospital de Santa Maria-CHLN, Lisbon, Portugal.
²⁷ Department of Neurology, Hospital San Rafael, Madrid, Spain.
²⁸ Neurology Department, Hospital de la Santa Creu i Sant Pau de Barcelona, Autonomous University of Barcelona, Barcelona, Spain.
²⁹ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
³⁰ Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
³¹ Emory ALS Center, Emory University School of Medicine, Atlanta, Georgia, USA.
³² Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh, UK.
³³ Centre for Neuroregeneration and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
³⁴ Faculty of Medicine, University of Southampton, Southampton, UK.
³⁵ Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
³⁶ Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
³⁷ Department of Clinical Neuroscience, Institute of Neurology, University College London, London, UK.
³⁸ Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK.
³⁹ Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK.
⁴⁰ Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London, UK.
⁴¹ North-East London and Essex Regional Motor Neuron Disease Care Centre, London, UK.
⁴² Department of Neurology, Hannover Medical School, Hannover, Germany.
⁴³ Department of Neurology, Otto von Güricke University Magdeburg, Magdeburg, Germany.
⁴⁴ Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.
⁴⁵ Department of Neurology, Charité University Hospital, Humboldt University, Berlin, Germany.
⁴⁶ Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
⁴⁷ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
⁴⁸ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
⁴⁹ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
⁵⁰ Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
⁵¹ Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵² Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵³ Neurodegeneration Research Laboratory, Bo[gcaron]aziçi University, Istanbul, Turkey.
⁵⁴ Neurology Department, Istanbul Medical School, Istanbul University, Istanbul, Turkey.
⁵⁵ Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
⁵⁶ INSERM U930, Université François Rabelais, Tours, France.
⁵⁷ AP-HP, Département de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁵⁸ UPMC, Pharmacologie, Paris VI, Paris, France.
⁵⁹ BESPIM, CHU de Nîmes, Nîmes, France.
⁶⁰ Department of Neurology, Ulm University, Ulm, Germany.
⁶¹ INSERM U1127, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶² CNRS UMR 7225, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶³ Sorbonne Universités, UPMC Paris 06, UMRS 1127, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶⁴ Institut du Cerveau et de la Moelle Epinière, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶⁵ AP-HP, Département de Génétique, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶⁶ Genethon, CNRS UMR 8587, Evry, France.
⁶⁷ Department of Medical Genetics, Institut du Cerveau et de la Moelle Epinière, Hôptial Pitié-Salpêtrière, Paris, France.
⁶⁸ Department of Neurogenetics, Institute of Neurology, University College London, London, UK.
⁶⁹ PopGen Biobank and Institute of Epidemiology, Christian Albrechts University Kiel, Kiel, Germany.
⁷⁰ Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
⁷¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Heidelberg, Germany.
⁷² Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁷³ Department of Genomics, Life and Brain Center, Bonn, Germany.
⁷⁴ Division of Medical Genetics, University Hospital Basel, University of Basel, Basel, Switzerland.
⁷⁵ Department of Biomedicine, University of Basel, Basel, Switzerland.
⁷⁶ Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Juelich, Germany.
⁷⁷ University of Lille, INSERM, CHU de Lille, Institut Pasteur de Lille, U1167-RID-AGE Risk Factor and Molecular Determinants of Aging Diseases, Lille, France.
⁷⁸ Bordeaux University, ISPED, Centre INSERM U1219-Epidemiologie Biostatistique et CIC-1401, CHU de Bordeaux, Pôle de Santé Publique, Bordeaux, France.
⁷⁹ Department of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
⁸⁰ Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
⁸¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁸² Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
⁸³ Department of Neurosciences, Experimental Neurology, Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, Belgium.
⁸⁴ Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.
⁸⁵ Laboratory of Experimental Neurobiology, IRCCS 'C. Mondino' National Institute of Neurology Foundation, Pavia, Italy.
⁸⁶ Neurologic Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁸⁷ Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, Università del Piemonte Orientale, Novara, Italy.
⁸⁸ Department of Neurosciences, University of Padova, Padova, Italy.
⁸⁹ Department of Neurology, Università del Piemonte Orientale, Novara, Italy.
⁹⁰ Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
⁹¹ 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
⁹² Azienda Ospedaliera Città della Salute e della Scienza, Turin, Italy.
⁹³ Department of Clinical Research in Neurology, University of Bari 'A. Moro' at Pia Fondazione 'Card. G. Panico', Tricase, Italy.
⁹⁴ NEMO Clinical Center, Serena Onlus Foundation, Niguarda Ca' Granda Hostipal, Milan, Italy.
⁹⁵ Medical Genetics Unit, Department of Laboratory Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.
⁹⁶ Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
⁹⁷ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁹⁸ Project MinE Foundation, Rotterdam, the Netherlands.
⁹⁹ Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
¹⁰⁰ University of Sydney, ANZAC Research Institute, Concord Hospital, Sydney, New South Wales, Australia.
¹⁰¹ Stacey MND Laboratory, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.
¹⁰² Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
¹⁰³ Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
¹⁰⁴ Institute of Human Genetics, Jena University Hospital, Jena, Germany.
¹⁰⁵ Department of Neurology, Brighton and Sussex Medical School Trafford Centre for Biomedical Research, University of Sussex, Falmer, UK.
¹⁰⁶ Laboratory of Neurological Diseases, Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
¹⁰⁷ Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
¹⁰⁸ Unit of Neurodegenerative Diseases, Department of Clinical Research in Neurology, University of Bari 'Aldo Moro' at Pia Fondazione Cardinale G. Panico, Tricase, Italy.
¹⁰⁹ Vesalius Research Center, Laboratory of Neurobiology, VIB, Leuven, Belgium.
¹¹⁰ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
¹¹¹ Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
¹¹² Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, USA.
¹¹³ Center for Basic Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.
¹¹⁴ Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
¹¹⁵ Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
¹¹⁶ Department of Pharmacology and Clinical Neurosience, Umeå University, Umeå, Sweden.
¹¹⁷ Centre SLA, CHRU de Tours, Tours, France.
¹¹⁸ Federation des Centres SLA Tours and Limoges, LITORALS, Tours, France.
¹¹⁹ Diamantina Institute, University of Queensland Translational Research Institute, Brisbane, Queensland, Australia.
¹²⁰ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
¹²¹ Department of Medical and Molecular Genetics, King's College London, London, UK.

PMID: 27455348
PMCID: PMC5556360
DOI: 10.1038/ng.3622

Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

**Figure 1**
Comparison of imputation accuracy. (a,b) Aggregate r2 values between imputed and sequenced genotypes on chromosome 20 are shown when using different reference panels for imputation. Allele frequencies were calculated from the Dutch samples included in the Genome of the Netherlands (GoNL) cohort. The highest imputation accuracy was achieved when imputing from the merged custom and 1000 Genomes Project (1000GP) panel. The difference in accuracy was most pronounced for low-frequency alleles (frequency 0.5–10%) in ALS cases from both the Netherlands (a) and the UK (b).

**Figure 2**
Meta-analysis and LMM associations. (a) Manhattan plot for the meta-analysis results. This approach yielded four genome-wide-significant associations. The associated SNP in *C21orf2* is a nonsynonymous variant not found to be associated in previous GWAS. (b) Manhattan plot for the LMM results. This analysis yielded three loci in addition to those identified by meta-analysis with associations that reached genome-wide significance (*MOBP*, *LOC101927815* and *SCFD1*). The association for SNPs in the previously identified ALS risk gene *TBK1* approached genome-wide significance (P = 6.6 × 10⁻⁸). As the *C21orf2* SNP was removed from a Swedish stratum because of MAF <1%, this SNP was tested separately, but it is presented here together with all SNPs with MAF >1% in all strata. *LOC101927815* is shown in gray because the association for this locus could not be replicated. Loci are labeled by the name of the nearest gene. The dotted lines correspond to the significance threshold of P = 5 × 10⁻⁸.

**Figure 3**
Partitioned heritability. (a) Heritability estimates for each chromosome were significantly correlated with chromosome length (P = 4.9 × 10⁻⁴). (b) For ALS, there was a clear trend where more heritability was explained by the low-frequency alleles. This effect was still observed when, for a fair comparison between ALS and a previous study partitioning heritability for schizophrenia (SCZ) using identical methods22, SNPs present in HapMap 3 (HM3) were included. Error bars correspond to standard errors.

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References

1. Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2011;7:639–649. - PubMed
1. Al-Chalabi A, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry. 2010;81:1324–1326. - PMC - PubMed
1. van Es MA, et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009;41:1083–1087. - PubMed
1. Laaksovirta H, et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 2010;9:978–985. - PMC - PubMed
1. Shatunov A, et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 2010;9:986–994. - PMC - PubMed

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[1] Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2011;7:639–649. - PubMed

[2] Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2011;7:639–649. - PubMed

[3] Al-Chalabi A, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry. 2010;81:1324–1326. - PMC - PubMed

[4] Al-Chalabi A, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry. 2010;81:1324–1326. - PMC - PubMed

[5] van Es MA, et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009;41:1083–1087. - PubMed

[6] van Es MA, et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009;41:1083–1087. - PubMed

[7] Laaksovirta H, et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 2010;9:978–985. - PMC - PubMed

[8] Laaksovirta H, et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 2010;9:978–985. - PMC - PubMed

[9] Shatunov A, et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 2010;9:986–994. - PMC - PubMed

[10] Shatunov A, et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 2010;9:986–994. - PMC - PubMed

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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

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