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Nat Genet. 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.

van Rheenen W1, Shatunov A2, Dekker AM1, McLaughlin RL3, Diekstra FP1, Pulit SL4, van der Spek RA1, Võsa U5, de Jong S6,7, Robinson MR8, Yang J8, Fogh I2,9, van Doormaal PT1, Tazelaar GH1, Koppers M1,10, Blokhuis AM1,10, Sproviero W2, Jones AR2, Kenna KP11, van Eijk KR1, Harschnitz O1,10, Schellevis RD1, Brands WJ1, Medic J1, Menelaou A4, Vajda A12,13, Ticozzi N9,14, Lin K2, Rogelj B15,16, Vrabec K17, Ravnik-Glavač M17,18, Koritnik B19, Zidar J19, Leonardis L19, Grošelj LD19, Millecamps S20, Salachas F20,21,22, Meininger V23,24, de Carvalho M25,26, Pinto S25,26, Mora JS27, Rojas-García R28,29, Polak M30,31, Chandran S32,33, Colville S32, Swingler R32, Morrison KE34, Shaw PJ35, Hardy J36, Orrell RW37, Pittman A36,38, Sidle K37, Fratta P39, Malaspina A40,41, Topp S2, Petri S42, Abdulla S43, Drepper C44, Sendtner M44, Meyer T45, Ophoff RA46,47,48, Staats KA48, Wiedau-Pazos M49, Lomen-Hoerth C50, Van Deerlin VM51, Trojanowski JQ51, Elman L52, McCluskey L52, Basak AN53, Tunca C53, Hamzeiy H53, Parman Y54, Meitinger T55, Lichtner P55, Radivojkov-Blagojevic M55, Andres CR56, Maurel C56, Bensimon G57,58,59, Landwehrmeyer B60, Brice A61,62,63,64,65, Payan CA57,59, Saker-Delye S66, Dürr A67, Wood NW68, Tittmann L69, Lieb W69, Franke A70, Rietschel M71, Cichon S72,73,74,75,76, Nöthen MM72,73, Amouyel P77, Tzourio C78, Dartigues JF78, Uitterlinden AG79,80, Rivadeneira F79,80, Estrada K79, Hofman A80,81, Curtis C6,7, Blauw HM1, van der Kooi AJ82, de Visser M82, Goris A83, Weber M84, Shaw CE2, Smith BN2, Pansarasa O85, Cereda C85, Del Bo R86, Comi GP86, D'Alfonso S87, Bertolin C88, Sorarù G88, Mazzini L89, Pensato V90, Gellera C90, Tiloca C9, Ratti A9,14, Calvo A91,92, Moglia C91,92, Brunetti M91,92, Arcuti S93, Capozzo R93, Zecca C93, Lunetta C94, Penco S95, Riva N96, Padovani A97, Filosto M97, Muller B98, Stuit RJ98; PARALS Registry; SLALOM Group; SLAP Registry; FALS Sequencing Consortium; SLAGEN Consortium; NNIPPS Study Group, Blair I99, Zhang K99, McCann EP99, Fifita JA99, Nicholson GA99,100, Rowe DB99, Pamphlett R101, Kiernan MC102, Grosskreutz J103, Witte OW103, Ringer T103, Prell T103, Stubendorff B103, Kurth I104, Hübner CA104, Leigh PN105, Casale F91, Chio A91,92, Beghi E106, Pupillo E106, Tortelli R93, Logroscino G107,108, Powell J2, Ludolph AC60, Weishaupt JH60, Robberecht W83,109,110, Van Damme P83,109,110, Franke L5, Pers TH111,112,113,114,115, Brown RH11, Glass JD30,31, Landers JE11, Hardiman O12,13, Andersen PM60,116, Corcia P56,117,118, Vourc'h P56, Silani V9,14, Wray NR8, Visscher PM8,119, de Bakker PI4,120, van Es MA1, Pasterkamp RJ10, Lewis CM6,121, Breen G6,7, Al-Chalabi A2, van den Berg LH1, Veldink JH1.

Author information

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.

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.

PMID:
27455348
PMCID:
PMC5556360
DOI:
10.1038/ng.3622
[Indexed for MEDLINE]
Free PMC Article

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