Letter | Published:

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

Nature Genetics volume 48, pages 10431048 (2016) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat. Rev. Neurol. 7, 639–649 (2011).

  2. 2.

    et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J. Neurol. Neurosurg. Psychiatry 81, 1324–1326 (2010).

  3. 3.

    et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat. Genet. 41, 1083–1087 (2009).

  4. 4.

    et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 9, 978–985 (2010).

  5. 5.

    et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 9, 986–994 (2010).

  6. 6.

    et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9orf72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

  7. 7.

    et al. A hexanucleotide repeat expansion in C9orf72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011).

  8. 8.

    et al. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Hum. Mol. Genet. 23, 2220–2231 (2014).

  9. 9.

    1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

  10. 10.

    Genome of the Netherlands Consortium. Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat. Genet. 46, 818–825 (2014).

  11. 11.

    , , , & Advantages and pitfalls in the application of mixed-model association methods. Nat. Genet. 46, 100–106 (2014).

  12. 12.

    et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

  13. 13.

    et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat. Genet. 43, 699–705 (2011).

  14. 14.

    et al. Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia. Neurology 83, 502–509 (2014).

  15. 15.

    et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015).

  16. 16.

    et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).

  17. 17.

    , , & Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

  18. 18.

    et al. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet. 6, e1000888 (2010).

  19. 19.

    et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat. Neurosci. 17, 1418–1428 (2014).

  20. 20.

    et al. Pitfalls of predicting complex traits from SNPs. Nat. Rev. Genet. 14, 507–515 (2013).

  21. 21.

    et al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J. Neurol. 253, 1642–1643 (2006).

  22. 22.

    et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat. Genet. 44, 247–250 (2012).

  23. 23.

    et al. Biological interpretation of genome-wide association studies using predicted gene functions. Nat. Commun. 6, 5890 (2015).

  24. 24.

    , & The SNARE complex in neuronal and sensory cells. Mol. Cell. Neurosci. 50, 58–69 (2012).

  25. 25.

    , , , & Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat. Rev. Neurol. 7, 616–630 (2011).

  26. 26.

    et al. Functional characterization of putative cilia genes by high-content analysis. Mol. Biol. Cell 22, 1104–1119 (2011).

  27. 27.

    , & Adenylyl cyclase type 3, a marker of primary cilia, is reduced in primary cell culture and in lumbar spinal cord in situ in G93A SOD1 mice. BMC Neurosci. 12, 71 (2011).

  28. 28.

    et al. Immunochemical characterization of a novel mitochondrially located protein encoded by a nuclear gene within the DFNB8/10 critical region on 21q22.3. Biochem. Biophys. Res. Commun. 238, 806–810 (1997).

  29. 29.

    et al. The NEK1 interactor, C21orf2, is required for efficient DNA damage repair. Acta Biochim. Biophys. Sin. (Shanghai) 47, 834–841 (2015).

  30. 30.

    , & Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons. Nat. Commun. 6, 7319 (2015).

  31. 31.

    et al. Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel. Nat. Commun. 5, 3934 (2014).

  32. 32.

    , & Genotype imputation with thousands of genomes. G3 (Bethesda) 1, 457–470 (2011).

Download references

Acknowledgements

The work of the contributing groups was supported by various grants from governmental and charitable bodies. Details are provided in the Supplementary Note.

Author information

Author notes

    • Wouter van Rheenen
    •  & Aleksey Shatunov

    These authors contributed equally to this work.

    • Ammar Al-Chalabi
    • , Leonard H van den Berg
    •  & Jan H Veldink

    These authors jointly directed this work.

Affiliations

  1. Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Wouter van Rheenen
    • , Annelot M Dekker
    • , Frank P Diekstra
    • , Rick A A van der Spek
    • , Perry TC van Doormaal
    • , Gijs H P Tazelaar
    • , Max Koppers
    • , Anna M Blokhuis
    • , Kristel R van Eijk
    • , Oliver Harschnitz
    • , Raymond D Schellevis
    • , William J Brands
    • , Jelena Medic
    • , Hylke M Blauw
    • , Michael A van Es
    • , Leonard H van den Berg
    •  & Jan H Veldink
  2. Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London, UK.

    • Aleksey Shatunov
    • , Isabella Fogh
    • , William Sproviero
    • , Ashley R Jones
    • , Kuang Lin
    • , Simon Topp
    • , Christopher E Shaw
    • , Bradley N Smith
    • , John Powell
    •  & Ammar Al-Chalabi
  3. Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.

    • Russell L McLaughlin
  4. Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Sara L Pulit
    • , Androniki Menelaou
    •  & Paul I W de Bakker
  5. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.

    • Urmo Võsa
    •  & Lude Franke
  6. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

    • Simone de Jong
    • , Charles Curtis
    • , Cathryn M Lewis
    •  & Gerome Breen
  7. NIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

    • Simone de Jong
    • , Charles Curtis
    •  & Gerome Breen
  8. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.

    • Matthew R Robinson
    • , Jian Yang
    • , Naomi R Wray
    •  & Peter M Visscher
  9. Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.

    • Isabella Fogh
    • , Nicola Ticozzi
    • , Cinzia Tiloca
    • , Antonia Ratti
    •  & Vincenzo Silani
  10. Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Max Koppers
    • , Anna M Blokhuis
    • , Oliver Harschnitz
    •  & R Jeroen Pasterkamp
  11. Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Kevin P Kenna
    • , Robert H Brown
    •  & John E Landers
  12. Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Ireland.

    • Alice Vajda
    •  & Orla Hardiman
  13. Department of Neurology, Beaumont Hospital, Dublin, Ireland.

    • Alice Vajda
    •  & Orla Hardiman
  14. Department of Pathophysiology and Tranplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.

    • Nicola Ticozzi
    • , Antonia Ratti
    •  & Vincenzo Silani
  15. Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.

    • Boris Rogelj
  16. Biomedical Research Institute BRIS, Ljubljana, Slovenia.

    • Boris Rogelj
  17. Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

    • Katarina Vrabec
    •  & Metka Ravnik-Glavač
  18. Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

    • Metka Ravnik-Glavač
  19. Ljubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.

    • Blaž Koritnik
    • , Janez Zidar
    • , Lea Leonardis
    •  & Leja Dolenc Grošelj
  20. Institut du Cerveau et de la Moelle Epinière, INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Paris, France.

    • Stéphanie Millecamps
    •  & François Salachas
  21. Centre de Référence Maladies Rares SLA Ile de France, Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France.

    • François Salachas
  22. GRC-UPMC SLA et Maladies du Motoneurone, Paris, France.

    • François Salachas
  23. Ramsay Generale de Santé, Hôpital Peupliers, Paris, France.

    • Vincent Meininger
  24. Réseau SLA Ile de France, Paris, France.

    • Vincent Meininger
  25. Institute of Physiology, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.

    • Mamede de Carvalho
    •  & Susana Pinto
  26. Department of Neurosciences, Hospital de Santa Maria–CHLN, Lisbon, Portugal.

    • Mamede de Carvalho
    •  & Susana Pinto
  27. Department of Neurology, Hospital San Rafael, Madrid, Spain.

    • Jesus S Mora
  28. Neurology Department, Hospital de la Santa Creu i Sant Pau de Barcelona, Autonomous University of Barcelona, Barcelona, Spain.

    • Ricardo Rojas-García
  29. Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

    • Ricardo Rojas-García
  30. Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Meraida Polak
    •  & Jonathan D Glass
  31. Emory ALS Center, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Meraida Polak
    •  & Jonathan D Glass
  32. Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh, UK.

    • Siddharthan Chandran
    • , Shuna Colville
    •  & Robert Swingler
  33. Centre for Neuroregeneration and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.

    • Siddharthan Chandran
  34. Faculty of Medicine, University of Southampton, Southampton, UK.

    • Karen E Morrison
  35. Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.

    • Pamela J Shaw
  36. Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.

    • John Hardy
    •  & Alan Pittman
  37. Department of Clinical Neuroscience, Institute of Neurology, University College London, London, UK.

    • Richard W Orrell
    •  & Katie Sidle
  38. Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK.

    • Alan Pittman
  39. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK.

    • Pietro Fratta
  40. Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London, UK.

    • Andrea Malaspina
  41. North-East London and Essex Regional Motor Neuron Disease Care Centre, London, UK.

    • Andrea Malaspina
  42. Department of Neurology, Hannover Medical School, Hannover, Germany.

    • Susanne Petri
  43. Department of Neurology, Otto von Güricke University Magdeburg, Magdeburg, Germany.

    • Susanne Abdulla
  44. Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.

    • Carsten Drepper
    •  & Michael Sendtner
  45. Department of Neurology, Charité University Hospital, Humboldt University, Berlin, Germany.

    • Thomas Meyer
  46. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Roel A Ophoff
  47. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Roel A Ophoff
  48. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.

    • Roel A Ophoff
    •  & Kim A Staats
  49. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Martina Wiedau-Pazos
  50. Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

    • Catherine Lomen-Hoerth
  51. Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Vivianna M Van Deerlin
    •  & John Q Trojanowski
  52. Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Lauren Elman
    •  & Leo McCluskey
  53. Neurodegeneration Research Laboratory, Boǧaziçi University, Istanbul, Turkey.

    • A Nazli Basak
    • , Ceren Tunca
    •  & Hamid Hamzeiy
  54. Neurology Department, Istanbul Medical School, Istanbul University, Istanbul, Turkey.

    • Yesim Parman
  55. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

    • Thomas Meitinger
    • , Peter Lichtner
    •  & Milena Radivojkov-Blagojevic
  56. INSERM U930, Université François Rabelais, Tours, France.

    • Christian R Andres
    • , Cindy Maurel
    • , Philippe Corcia
    •  & Patrick Vourc'h
  57. AP-HP, Département de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, Paris, France.

    • Gilbert Bensimon
    •  & Christine A M Payan
  58. UPMC, Pharmacologie, Paris VI, Paris, France.

    • Gilbert Bensimon
  59. BESPIM, CHU de Nîmes, Nîmes, France.

    • Gilbert Bensimon
    •  & Christine A M Payan
  60. Department of Neurology, Ulm University, Ulm, Germany.

    • Bernhard Landwehrmeyer
    • , Albert C Ludolph
    • , Jochen H Weishaupt
    •  & Peter M Andersen
  61. INSERM U1127, Hôpital de la Pitié-Salpêtrière, Paris, France.

    • Alexis Brice
  62. CNRS UMR 7225, Hôpital de la Pitié-Salpêtrière, Paris, France.

    • Alexis Brice
  63. Sorbonne Universités, UPMC Paris 06, UMRS 1127, Hôpital de la Pitié-Salpêtrière, Paris, France.

    • Alexis Brice
  64. Institut du Cerveau et de la Moelle Epinière, Hôpital de la Pitié-Salpêtrière, Paris, France.

    • Alexis Brice
  65. AP-HP, Département de Génétique, Hôpital de la Pitié-Salpêtrière, Paris, France.

    • Alexis Brice
  66. Genethon, CNRS UMR 8587, Evry, France.

    • Safaa Saker-Delye
  67. Department of Medical Genetics, Institut du Cerveau et de la Moelle Epinière, Hôptial Pitié-Salpêtrière, Paris, France.

    • Alexandra Dürr
  68. Department of Neurogenetics, Institute of Neurology, University College London, London, UK.

    • Nicholas W Wood
  69. PopGen Biobank and Institute of Epidemiology, Christian Albrechts University Kiel, Kiel, Germany.

    • Lukas Tittmann
    •  & Wolfgang Lieb
  70. Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.

    • Andre Franke
  71. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Heidelberg, Germany.

    • Marcella Rietschel
  72. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Sven Cichon
    •  & Markus M Nöthen
  73. Department of Genomics, Life and Brain Center, Bonn, Germany.

    • Sven Cichon
    •  & Markus M Nöthen
  74. Division of Medical Genetics, University Hospital Basel, University of Basel, Basel, Switzerland.

    • Sven Cichon
  75. Department of Biomedicine, University of Basel, Basel, Switzerland.

    • Sven Cichon
  76. Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Juelich, Germany.

    • Sven Cichon
  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.

    • Philippe Amouyel
  78. Bordeaux University, ISPED, Centre INSERM U1219–Epidemiologie Biostatistique et CIC-1401, CHU de Bordeaux, Pôle de Santé Publique, Bordeaux, France.

    • Christophe Tzourio
    •  & Jean-François Dartigues
  79. Department of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Andre G Uitterlinden
    • , Fernando Rivadeneira
    •  & Karol Estrada
  80. Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Andre G Uitterlinden
    • , Fernando Rivadeneira
    •  & Albert Hofman
  81. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Albert Hofman
  82. Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

    • Anneke J van der Kooi
    •  & Marianne de Visser
  83. Department of Neurosciences, Experimental Neurology, Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven–University of Leuven, Leuven, Belgium.

    • An Goris
    • , Wim Robberecht
    •  & Philip Van Damme
  84. Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.

    • Markus Weber
  85. Laboratory of Experimental Neurobiology, IRCCS 'C. Mondino' National Institute of Neurology Foundation, Pavia, Italy.

    • Orietta Pansarasa
    •  & Cristina Cereda
  86. Neurologic Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

    • Roberto Del Bo
    •  & Giacomo P Comi
  87. Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, Università del Piemonte Orientale, Novara, Italy.

    • Sandra D'Alfonso
  88. Department of Neurosciences, University of Padova, Padova, Italy.

    • Cinzia Bertolin
    •  & Gianni Sorarù
  89. Department of Neurology, Università del Piemonte Orientale, Novara, Italy.

    • Letizia Mazzini
  90. Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.

    • Viviana Pensato
    •  & Cinzia Gellera
  91. 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.

    • Andrea Calvo
    • , Cristina Moglia
    • , Maura Brunetti
    • , Federico Casale
    •  & Adriano Chio
  92. Azienda Ospedaliera Città della Salute e della Scienza, Turin, Italy.

    • Andrea Calvo
    • , Cristina Moglia
    • , Maura Brunetti
    •  & Adriano Chio
  93. Department of Clinical Research in Neurology, University of Bari 'A. Moro' at Pia Fondazione 'Card. G. Panico', Tricase, Italy.

    • Simona Arcuti
    • , Rosa Capozzo
    • , Chiara Zecca
    •  & Rosanna Tortelli
  94. NEMO Clinical Center, Serena Onlus Foundation, Niguarda Ca' Granda Hostipal, Milan, Italy.

    • Christian Lunetta
  95. Medical Genetics Unit, Department of Laboratory Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.

    • Silvana Penco
  96. Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

    • Nilo Riva
  97. Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

    • Alessandro Padovani
    •  & Massimiliano Filosto
  98. Project MinE Foundation, Rotterdam, the Netherlands.

    • Bernard Muller
    •  & Robbert Jan Stuit
  99. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.

    • Ian Blair
    • , Katharine Zhang
    • , Emily P McCann
    • , Jennifer A Fifita
    • , Garth A Nicholson
    •  & Dominic B Rowe
  100. University of Sydney, ANZAC Research Institute, Concord Hospital, Sydney, New South Wales, Australia.

    • Garth A Nicholson
  101. Stacey MND Laboratory, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.

    • Roger Pamphlett
  102. Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.

    • Matthew C Kiernan
  103. Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.

    • Julian Grosskreutz
    • , Otto W Witte
    • , Thomas Ringer
    • , Tino Prell
    •  & Beatrice Stubendorff
  104. Institute of Human Genetics, Jena University Hospital, Jena, Germany.

    • Ingo Kurth
    •  & Christian A Hübner
  105. Department of Neurology, Brighton and Sussex Medical School Trafford Centre for Biomedical Research, University of Sussex, Falmer, UK.

    • P Nigel Leigh
  106. Laboratory of Neurological Diseases, Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

    • Ettore Beghi
    •  & Elisabetta Pupillo
  107. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.

    • Giancarlo Logroscino
  108. Unit of Neurodegenerative Diseases, Department of Clinical Research in Neurology, University of Bari 'Aldo Moro' at Pia Fondazione Cardinale G. Panico, Tricase, Italy.

    • Giancarlo Logroscino
  109. Vesalius Research Center, Laboratory of Neurobiology, VIB, Leuven, Belgium.

    • Wim Robberecht
    •  & Philip Van Damme
  110. Department of Neurology, University Hospitals Leuven, Leuven, Belgium.

    • Wim Robberecht
    •  & Philip Van Damme
  111. Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Tune H Pers
  112. Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Tune H Pers
  113. Center for Basic Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Tune H Pers
  114. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Tune H Pers
  115. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Tune H Pers
  116. Department of Pharmacology and Clinical Neurosience, Umeå University, Umeå, Sweden.

    • Peter M Andersen
  117. Centre SLA, CHRU de Tours, Tours, France.

    • Philippe Corcia
  118. Federation des Centres SLA Tours and Limoges, LITORALS, Tours, France.

    • Philippe Corcia
  119. Diamantina Institute, University of Queensland Translational Research Institute, Brisbane, Queensland, Australia.

    • Peter M Visscher
  120. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker
  121. Department of Medical and Molecular Genetics, King's College London, London, UK.

    • Cathryn M Lewis

Consortia

  1. PARALS Registry

    A list of members appears in the Supplementary Note.

  2. SLALOM Group

    A list of members appears in the Supplementary Note.

  3. SLAP Registry

    A list of members appears in the Supplementary Note.

  4. FALS Sequencing Consortium

    A list of members appears in the Supplementary Note.

  5. SLAGEN Consortium

    A list of members appears in the Supplementary Note.

  6. NNIPPS Study Group

    A list of members appears in the Supplementary Note.

Authors

  1. Search for Wouter van Rheenen in:

  2. Search for Aleksey Shatunov in:

  3. Search for Annelot M Dekker in:

  4. Search for Russell L McLaughlin in:

  5. Search for Frank P Diekstra in:

  6. Search for Sara L Pulit in:

  7. Search for Rick A A van der Spek in:

  8. Search for Urmo Võsa in:

  9. Search for Simone de Jong in:

  10. Search for Matthew R Robinson in:

  11. Search for Jian Yang in:

  12. Search for Isabella Fogh in:

  13. Search for Perry TC van Doormaal in:

  14. Search for Gijs H P Tazelaar in:

  15. Search for Max Koppers in:

  16. Search for Anna M Blokhuis in:

  17. Search for William Sproviero in:

  18. Search for Ashley R Jones in:

  19. Search for Kevin P Kenna in:

  20. Search for Kristel R van Eijk in:

  21. Search for Oliver Harschnitz in:

  22. Search for Raymond D Schellevis in:

  23. Search for William J Brands in:

  24. Search for Jelena Medic in:

  25. Search for Androniki Menelaou in:

  26. Search for Alice Vajda in:

  27. Search for Nicola Ticozzi in:

  28. Search for Kuang Lin in:

  29. Search for Boris Rogelj in:

  30. Search for Katarina Vrabec in:

  31. Search for Metka Ravnik-Glavač in:

  32. Search for Blaž Koritnik in:

  33. Search for Janez Zidar in:

  34. Search for Lea Leonardis in:

  35. Search for Leja Dolenc Grošelj in:

  36. Search for Stéphanie Millecamps in:

  37. Search for François Salachas in:

  38. Search for Vincent Meininger in:

  39. Search for Mamede de Carvalho in:

  40. Search for Susana Pinto in:

  41. Search for Jesus S Mora in:

  42. Search for Ricardo Rojas-García in:

  43. Search for Meraida Polak in:

  44. Search for Siddharthan Chandran in:

  45. Search for Shuna Colville in:

  46. Search for Robert Swingler in:

  47. Search for Karen E Morrison in:

  48. Search for Pamela J Shaw in:

  49. Search for John Hardy in:

  50. Search for Richard W Orrell in:

  51. Search for Alan Pittman in:

  52. Search for Katie Sidle in:

  53. Search for Pietro Fratta in:

  54. Search for Andrea Malaspina in:

  55. Search for Simon Topp in:

  56. Search for Susanne Petri in:

  57. Search for Susanne Abdulla in:

  58. Search for Carsten Drepper in:

  59. Search for Michael Sendtner in:

  60. Search for Thomas Meyer in:

  61. Search for Roel A Ophoff in:

  62. Search for Kim A Staats in:

  63. Search for Martina Wiedau-Pazos in:

  64. Search for Catherine Lomen-Hoerth in:

  65. Search for Vivianna M Van Deerlin in:

  66. Search for John Q Trojanowski in:

  67. Search for Lauren Elman in:

  68. Search for Leo McCluskey in:

  69. Search for A Nazli Basak in:

  70. Search for Ceren Tunca in:

  71. Search for Hamid Hamzeiy in:

  72. Search for Yesim Parman in:

  73. Search for Thomas Meitinger in:

  74. Search for Peter Lichtner in:

  75. Search for Milena Radivojkov-Blagojevic in:

  76. Search for Christian R Andres in:

  77. Search for Cindy Maurel in:

  78. Search for Gilbert Bensimon in:

  79. Search for Bernhard Landwehrmeyer in:

  80. Search for Alexis Brice in:

  81. Search for Christine A M Payan in:

  82. Search for Safaa Saker-Delye in:

  83. Search for Alexandra Dürr in:

  84. Search for Nicholas W Wood in:

  85. Search for Lukas Tittmann in:

  86. Search for Wolfgang Lieb in:

  87. Search for Andre Franke in:

  88. Search for Marcella Rietschel in:

  89. Search for Sven Cichon in:

  90. Search for Markus M Nöthen in:

  91. Search for Philippe Amouyel in:

  92. Search for Christophe Tzourio in:

  93. Search for Jean-François Dartigues in:

  94. Search for Andre G Uitterlinden in:

  95. Search for Fernando Rivadeneira in:

  96. Search for Karol Estrada in:

  97. Search for Albert Hofman in:

  98. Search for Charles Curtis in:

  99. Search for Hylke M Blauw in:

  100. Search for Anneke J van der Kooi in:

  101. Search for Marianne de Visser in:

  102. Search for An Goris in:

  103. Search for Markus Weber in:

  104. Search for Christopher E Shaw in:

  105. Search for Bradley N Smith in:

  106. Search for Orietta Pansarasa in:

  107. Search for Cristina Cereda in:

  108. Search for Roberto Del Bo in:

  109. Search for Giacomo P Comi in:

  110. Search for Sandra D'Alfonso in:

  111. Search for Cinzia Bertolin in:

  112. Search for Gianni Sorarù in:

  113. Search for Letizia Mazzini in:

  114. Search for Viviana Pensato in:

  115. Search for Cinzia Gellera in:

  116. Search for Cinzia Tiloca in:

  117. Search for Antonia Ratti in:

  118. Search for Andrea Calvo in:

  119. Search for Cristina Moglia in:

  120. Search for Maura Brunetti in:

  121. Search for Simona Arcuti in:

  122. Search for Rosa Capozzo in:

  123. Search for Chiara Zecca in:

  124. Search for Christian Lunetta in:

  125. Search for Silvana Penco in:

  126. Search for Nilo Riva in:

  127. Search for Alessandro Padovani in:

  128. Search for Massimiliano Filosto in:

  129. Search for Bernard Muller in:

  130. Search for Robbert Jan Stuit in:

  131. Search for Ian Blair in:

  132. Search for Katharine Zhang in:

  133. Search for Emily P McCann in:

  134. Search for Jennifer A Fifita in:

  135. Search for Garth A Nicholson in:

  136. Search for Dominic B Rowe in:

  137. Search for Roger Pamphlett in:

  138. Search for Matthew C Kiernan in:

  139. Search for Julian Grosskreutz in:

  140. Search for Otto W Witte in:

  141. Search for Thomas Ringer in:

  142. Search for Tino Prell in:

  143. Search for Beatrice Stubendorff in:

  144. Search for Ingo Kurth in:

  145. Search for Christian A Hübner in:

  146. Search for P Nigel Leigh in:

  147. Search for Federico Casale in:

  148. Search for Adriano Chio in:

  149. Search for Ettore Beghi in:

  150. Search for Elisabetta Pupillo in:

  151. Search for Rosanna Tortelli in:

  152. Search for Giancarlo Logroscino in:

  153. Search for John Powell in:

  154. Search for Albert C Ludolph in:

  155. Search for Jochen H Weishaupt in:

  156. Search for Wim Robberecht in:

  157. Search for Philip Van Damme in:

  158. Search for Lude Franke in:

  159. Search for Tune H Pers in:

  160. Search for Robert H Brown in:

  161. Search for Jonathan D Glass in:

  162. Search for John E Landers in:

  163. Search for Orla Hardiman in:

  164. Search for Peter M Andersen in:

  165. Search for Philippe Corcia in:

  166. Search for Patrick Vourc'h in:

  167. Search for Vincenzo Silani in:

  168. Search for Naomi R Wray in:

  169. Search for Peter M Visscher in:

  170. Search for Paul I W de Bakker in:

  171. Search for Michael A van Es in:

  172. Search for R Jeroen Pasterkamp in:

  173. Search for Cathryn M Lewis in:

  174. Search for Gerome Breen in:

  175. Search for Ammar Al-Chalabi in:

  176. Search for Leonard H van den Berg in:

  177. Search for Jan H Veldink in:

Contributions

A.V., N.T., K.L., B.R., K.V., M.R.-G., B.K., J.Z., L.L., L.D.G., S.M., F.S., V.M., M.d.C., S. Pinto, J.S.M., R.R.-G., M.P., S. Chandran, S. Colville, R.S., K.E.M., P.J.S., J.H., R.W.O., A. Pittman, K.S., P.F., A. Malaspina, S.T., S. Petri, S. Abdulla, C.D., M.S., T. Meyer, R.A.O., K.A.S., M.W.-P., C.L.-H., V.M.V.D., J.Q.T., L.E., L. McCluskey, A.N.B., Y.P., T. Meitinger, P.L., M.R.-B., C.R.A., C. Maurel, G. Bensimon, B.L., A.B., C.A.M.P., S.S.-D., A.D., N.W.W., L.T., W.L., A.F., M.R., S. Cichon, M.M.N., P.A., C. Tzourio, J.-F.D., A.G.U., F.R., K.E., A.H., C. Curtis, H.M.B., A.J.v.d.K., M.d.V., A.G., M.W., C.E.S., B.N.S., O.P., C. Cereda, R.D.B., G.P.C., S.D'A., C.B., G.S., L. Mazzini, V.P., C.G., C. Tiloca, A.R., A. Calvo, C. Moglia, M.B., S. Arcuti, R.C., C.Z., C.L., S. Penco, N.R., A. Padovani, M.F., B.M., R.J.S., PARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group, I.B., G.A.N., D.B.R., R.P., M.C.K., J.G., O.W.W., T.R., B.S., I.K., C.A.H., P.N.L., F.C., A. Chìo, E.B., E.P., R.T., G.L., J.P., A.C.L., J.H.W., W.R., P.V.D., L.F., T.P., R.H.B., J.D.G., J.E.L., O. Hardiman, P.M.A., P.C., P.V., V.S., M.A.v.E., A.A.-C., L.H.v.d.B. and J.H.V. were involved in phenotyping, sample collection and management. W.v.R., A.S., A.M.D., R.L.M., F.P.D., R.A.A.v.d.S., P.T.C.v.D., G.H.P.T., M.K., A.M.B., W.S., A.R.J., K.P.K., I.F., A.V., N.T., R.D.S., W.J.B., A.V., K.V., M.R.-G., B.K., L.L., S. Abdulla, K.S., E.P., F.P.D., J.M., C. Curtis, G. Breen, A.A.-C. and J.H.V. prepared DNA and performed SNP array hybridizations. W.v.R., S.L.P., K.P.K., K.L., A.M.D., P.T.C.v.D., G.H.P.T., K.R.v.E., P.I.W.d.B. and J.H.V. were involved in the next-generation sequencing analyses. W.v.R., K.R.v.E., A. Menelaou, P.I.W.d.B., A.A.-C. and J.H.V. performed the imputation. W.v.R., A.S., F.P.D., R.L.M., S.L.P., S.d.J., I.F., N.T., W.S., A.R.J., K.P.K., K.R.v.E., K.S., H.M.B., P.I.W.d.B., M.A.v.E., C.M.L., G. Breen, A.A.-C., L.H.v.d.B. and J.H.V. performed GWAS analyses. W.v.R., A.M.D., R.A.A.v.d.S., R.L.M., C.R.A., M.K., A.M.B., R.D.S., E.P.M., J.A.F., C. Tunca, H.H., K.Z., P.C., P.V. and J.H.V. performed the replication analyses. W.v.R., A.S., R.L.M., M.R.R., J.Y., N.R.W., P.M.V., C.M.L., A.A.-C. and J.H.V. performed polygenic risk scoring and heritability analyses. S.d.J., U.V., L.F., T.H.P., W.v.R., O. Harschnitz, G. Breen, R.J.P. and J.H.V. performed biological pathway analyses. U.V., L.F., W.v.R. and J.H.V. performed eQTL analyses. W.v.R., A.S., A.A.-C., L.H.v.d.B. and J.H.V. prepared the manuscript with contributions from all authors. A.A.-C., L.H.v.d.B. and J.H.V. directed the study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ammar Al-Chalabi or Jan H Veldink.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14, Supplementary Tables 1–20 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Data Set: Brain cis-eQTLs.

    Overlap with previously identified brain cis-eQTLs for all SNPs in the genome-wide-significant loci.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3622

Further reading