Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Display options

Format

Share it on

Nat Genet. 2021 Dec;53(12):1636-1648. doi: 10.1038/s41588-021-00973-1. Epub 2021 Dec 06.

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Nature genetics

Wouter van Rheenen, Rick A A van der Spek, Mark K Bakker, Joke J F A van Vugt, Paul J Hop, Ramona A J Zwamborn, Niek de Klein, Harm-Jan Westra, Olivier B Bakker, Patrick Deelen, Gemma Shireby, Eilis Hannon, Matthieu Moisse, Denis Baird, Restuadi Restuadi, Egor Dolzhenko, Annelot M Dekker, Klara Gawor, Henk-Jan Westeneng, Gijs H P Tazelaar, Kristel R van Eijk, Maarten Kooyman, Ross P Byrne, Mark Doherty, Mark Heverin, Ahmad Al Khleifat, Alfredo Iacoangeli, Aleksey Shatunov, Nicola Ticozzi, Johnathan Cooper-Knock, Bradley N Smith, Marta Gromicho, Siddharthan Chandran, Suvankar Pal, Karen E Morrison, Pamela J Shaw, John Hardy, Richard W Orrell, Michael Sendtner, Thomas Meyer, Nazli Başak, Anneke J van der Kooi, Antonia Ratti, Isabella Fogh, Cinzia Gellera, Giuseppe Lauria, Stefania Corti, Cristina Cereda, Daisy Sproviero, Sandra D'Alfonso, Gianni Sorarù, Gabriele Siciliano, Massimiliano Filosto, Alessandro Padovani, Adriano Chiò, Andrea Calvo, Cristina Moglia, Maura Brunetti, Antonio Canosa, Maurizio Grassano, Ettore Beghi, Elisabetta Pupillo, Giancarlo Logroscino, Beatrice Nefussy, Alma Osmanovic, Angelica Nordin, Yossef Lerner, Michal Zabari, Marc Gotkine, Robert H Baloh, Shaughn Bell, Patrick Vourc'h, Philippe Corcia, Philippe Couratier, Stéphanie Millecamps, Vincent Meininger, François Salachas, Jesus S Mora Pardina, Abdelilah Assialioui, Ricardo Rojas-García, Patrick A Dion, Jay P Ross, Albert C Ludolph, Jochen H Weishaupt, David Brenner, Axel Freischmidt, Gilbert Bensimon, Alexis Brice, Alexandra Durr, Christine A M Payan, Safa Saker-Delye, Nicholas W Wood, Simon Topp, Rosa Rademakers, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Stephan Ripke, Alice Braun, Julia Kraft, David C Whiteman, Catherine M Olsen, Andre G Uitterlinden, Albert Hofman, Marcella Rietschel, Sven Cichon, Markus M Nöthen, Philippe Amouyel, Bryan J Traynor, Andrew B Singleton, Miguel Mitne Neto, Ruben J Cauchi, Roel A Ophoff, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna M van Deerlin, Julian Grosskreutz, Annekathrin Roediger, Nayana Gaur, Alexander Jörk, Tabea Barthel, Erik Theele, Benjamin Ilse, Beatrice Stubendorff, Otto W Witte, Robert Steinbach, Christian A Hübner, Caroline Graff, Lev Brylev, Vera Fominykh, Vera Demeshonok, Anastasia Ataulina, Boris Rogelj, Blaž Koritnik, Janez Zidar, Metka Ravnik-Glavač, Damjan Glavač, Zorica Stević, Vivian Drory, Monica Povedano, Ian P Blair, Matthew C Kiernan, Beben Benyamin, Robert D Henderson, Sarah Furlong, Susan Mathers, Pamela A McCombe, Merrilee Needham, Shyuan T Ngo, Garth A Nicholson, Roger Pamphlett, Dominic B Rowe, Frederik J Steyn, Kelly L Williams, Karen A Mather, Perminder S Sachdev, Anjali K Henders, Leanne Wallace, Mamede de Carvalho, Susana Pinto, Susanne Petri, Markus Weber, Guy A Rouleau, Vincenzo Silani, Charles J Curtis, Gerome Breen, Jonathan D Glass, Robert H Brown, John E Landers, Christopher E Shaw, Peter M Andersen, Ewout J N Groen, Michael A van Es, R Jeroen Pasterkamp, Dongsheng Fan, Fleur C Garton, Allan F McRae, George Davey Smith, Tom R Gaunt, Michael A Eberle, Jonathan Mill, Russell L McLaughlin, Orla Hardiman, Kevin P Kenna, Naomi R Wray, Ellen Tsai, Heiko Runz, Lude Franke, Ammar Al-Chalabi, Philip Van Damme, Leonard H van den Berg, Jan H Veldink

Affiliations

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. [email protected].
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.
Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, Leuven, Belgium.
Laboratory of Neurobiology, VIB, Center for Brain & Disease Research, Leuven, Belgium.
Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
Translational Biology, Biogen, Boston, MA, USA.
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, UK.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Illumina, San Diego, CA, USA.
Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
National Institute for Health Research Biomedical Research Centre and Dementia Unit, South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
Department of Neurology, Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milan, Italy.
Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Euan MacDonald Centre for Motor Neurone Disease Research, Edinburgh, UK.
UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.
Charité University Hospital, Humboldt University, Berlin, Germany.
Neurodegeneration Research Laboratory, Bogazici University, Istanbul, Turkey.
Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands.
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', MIlan, Italy.
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
Department of Neurosciences, University of Padova, Padova, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Neurologia 1, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
Laboratory of Neurological Diseases, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Department of Clinical Research in Neurology, University of Bari at 'Pia Fondazione Card G. Panico' Hospital, Bari, Italy.
Neuromuscular Diseases Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Department of Neurology, Hannover Medical School, Hannover, Germany.
Essener Zentrum für Seltene Erkrankungen (EZSE), University Hospital Essen, Essen, Germany.
Department of Clinical Sciences, Neurosciences, Umeå University, Umeå, Sweden.
Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Neurology, the Agnes Ginges Center for Human Neurogenetics, Hadassah Medical Center, Jerusalem, Israel.
Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Neurology, Neuromuscular Division, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Service de Biochimie et Biologie Moléculaire, CHU de Tours, Tours, France.
UMR 1253, Université de Tours, Inserm, Tours, France.
Centre de référence sur la SLA, CHU de Tours, Tours, France.
Centre de référence sur la SLA, CHRU de Limoges, Limoges, France.
UMR 1094, Université de Limoges, Inserm, Limoges, France.
ICM, Institut du Cerveau, Inserm, CNRS, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Hôpital des Peupliers, Ramsay Générale de Santé, Paris, France.
Département de Neurologie, Centre de référence SLA Ile de France, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.
ALS Unit, Hospital San Rafael, Madrid, Spain.
Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain.
MND Clinic, Neurology Department, Hospital de la Santa Creu i Sant Pau de Barcelona, Universitat Autonoma de Barcelona, Barcelona, Spain.
Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Department of Neurology, Ulm University, Ulm, Germany.
Division of Neurodegeneration, Department of Neurology, University Medicine Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
German Center for Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany.
Département de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, UPMC Pharmacologie, AP-HP, Paris, France.
Pharmacologie Sorbonne Université, Paris, France.
Institut du Cerveau, Paris Brain Institute ICM, Paris, France.
Laboratoire de Biostatistique, Epidémiologie Clinique, Santé Publique Innovation et Méthodologie (BESPIM), CHU-Nîmes, Nîmes, France.
Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France.
Genethon, CNRS UMR, Evry, France.
Department of Clinical and Movement Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
Popgen Biobank and Institute of Epidemiology, Christian Albrechts-University Kiel, Kiel, Germany.
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
Cancer Control Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Department of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Central Institute of Mental Health, Mannheim, Germany.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Genomics, Life and Brain Center, Bonn, Germany.
Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Juelich, Germany.
INSERM UMR1167-RID-AGE LabEx DISTALZ-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille, Centre Hospitalier of the University of Lille, Institut Pasteur de Lille, Lille, France.
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, USA.
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, USA.
Universidade de São Paulo, São Paulo, Brazil.
Centre for Molecular Medicine and Biobanking and Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, the Netherlands.
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Department of Neurology, University of California, San Francisco, CA, USA.
Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Precision Neurology Unit, Department of Neurology, University Hospital Schleswig-Holstein, University of Luebeck, Luebeck, Germany.
Institute of Human Genetics, Jena University Hospital, Jena, Germany.
Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Department of Neurology, Bujanov Moscow Clinical Hospital, Moscow, Russia.
Moscow Research and Clinical Center for Neuropsychiatry of the Healthcare Department, Moscow, Russia.
Department of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology Russian Academy of Sciences, Moscow, Russia.
ALS-Care Center, 'GAOORDI', Medical Clinic of the St. Petersburg, St. Petersburg, Russia.
Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
Biomedical Research Institute BRIS, Ljubljana, Slovenia.
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
Ljubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Clinic of Neurology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
Australian Centre for Precision Health and Allied Health and Human Performance, University of South Australia, Adelaide, South Australia, Australia.
Centre for Clinical Research, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia.
Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Calvary Health Care Bethlehem, Parkdale, Victoria, Australia.
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
Fiona Stanley Hospital, Perth, Western Australia, Australia.
Notre Dame University, Fremantle, Western Australia, Australia.
Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Perth, Western Australia, Australia.
Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.
Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
Discipline of Pathology and Department of Neuropathology, Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
The School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
Neuroscience Research Australia Institute, Randwick, New South Wales, Australia.
Neuropsychiatric Institute, the Prince of Wales Hospital, UNSW, Randwick, New South Wales, Australia.
Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
Department Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Department of Neurology, Third Hospital, Peking University, Beijing, China.
Population Health Science, Bristol Medical School, Bristol, UK.
King's College Hospital, London, UK.
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. [email protected].

PMID: 34873335 DOI: 10.1038/s41588-021-00973-1

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

References

van Es, M. A. et al. Amyotrophic lateral sclerosis. Lancet 390, 2084–2098 (2017). - PubMed
Al-Chalabi, A., van den Berg, L. H. & Veldink, J. H. Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat. Rev. Neurol. 13, 96–104 (2017). - PubMed
Trabjerg, B. B. et al. ALS in Danish registries: heritability and links to psychiatric and cardiovascular disorders. Neurol. Genet. 6, e398 (2020). - PubMed
Ryan, M., Heverin, M., McLaughlin, R. L. & Hardiman, O. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 76, 1367–1374 (2019). - PubMed
Byrne, S., Elamin, M., Bede, P. & Hardiman, O. Absence of consensus in diagnostic criteria for familial neurodegenerative diseases. J. Neurol. Neurosurg. Psychiatry 83, 365–367 (2012). - PubMed
Cirulli, E. T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015). - PubMed
Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015). - PubMed
Kenna, K. P. et al. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat. Genet. 48, 1037–1042 (2016). - PubMed
Brenner, D. et al. NEK1 mutations in familial amyotrophic lateral sclerosis. Brain 139, e28 (2016). - PubMed
Majounie, E. et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 11, 323–330 (2012). - PubMed
Nicolas, A. et al. Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron 97, 1268–1283 (2018). - PubMed
van Es, M. A. 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). - PubMed
Laaksovirta, H. et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 9, 978–985 (2010). - PubMed
van Rheenen, W. et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat. Genet. 48, 1043–1048 (2016). - PubMed
Benyamin, B. et al. Cross-ethnic meta-analysis identifies association of the GPX3–TNIP1 locus with amyotrophic lateral sclerosis. Nat. Commun. 8, 611 (2017). - PubMed
Nakamura, R. et al. A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. Commun. Biol. 3, 526 (2020). - PubMed
DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011). - PubMed
Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS–FTD. Neuron 72, 257–268 (2011). - PubMed
Diekstra, F. P. et al. C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis. Ann. Neurol. 76, 120–133 (2014). - PubMed
Chen, J. A. et al. Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol. Neurodegener. 13, 41 (2018). - PubMed
McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016). - PubMed
Iacoangeli, A. et al. Genome-wide meta-analysis finds the ACSL5–ZDHHC6 locus is associated with ALS and links weight loss to the disease genetics. Cell Rep. 33, 108323 (2020). - PubMed
Võsa, U. et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat. Genet. 53, 1300–1310 (2021). - PubMed
de Klein, N. et al. Brain expression quantitative trait locus and network analysis reveals downstream effects and putative drivers for brain-related diseases. Preprint at bioRxiv https://doi.org/10.1101/2021.03.01.433439 (2021). - PubMed
Pidsley, R. et al. Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling. Genome Biol. 17, 208 (2016). - PubMed
Shireby, G. L. et al. Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex. Brain 143, 3763–3775 (2020). - PubMed
Hannon, E. et al. An integrated genetic–epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol. 17, 176 (2016). - PubMed
Fang, X. et al. The NEK1 interactor, C21ORF2, is required for efficient DNA damage repair. Acta Biochim. Biophys. Sin. 47, 834–841 (2015). - PubMed
Brown, A.-L. et al. Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization. Preprint at bioRxiv https://doi.org/10.1101/2021.04.02.438170 (2021). - PubMed
Ma, X. R. et al. TDP-43 represses cryptic exon inclusion in FTD/ALS gene UNC13A. Preprint at bioRxiv https://doi.org/10.1101/2021.04.02.438213 (2021). - PubMed
Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat. Genet. 51, 404–413 (2019). - PubMed
Leeuw, C. A., de Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219 (2015). - PubMed
Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017). - PubMed
Watanabe, K., Umićević Mirkov, M., de Leeuw, C. A., van den Heuvel, M. P. & Posthuma, D. Genetic mapping of cell type specificity for complex traits. Nat. Commun. 10, 3222 (2019). - PubMed
Deelen, P. et al. Improving the diagnostic yield of exome-sequencing by predicting gene–phenotype associations using large-scale gene expression analysis. Nat. Commun. 10, 2837 (2019). - PubMed
Hop, P. J. et al. Genome-wide study of DNA methylation in amyotrophic lateral sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways. Preprint at medRxiv https://doi.org/10.1101/2021.03.12.21253115 (2021). - PubMed
Davies, N. M., Holmes, M. V. & Smith, G. D. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 362, k601 (2018). - PubMed
Bowden, J. et al. Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the radial plot and radial regression. Int. J. Epidemiol. 47, 1264–1278 (2018). - PubMed
Munafò, M. R., Tilling, K., Taylor, A. E., Evans, D. M. & Davey Smith, G. Collider scope: when selection bias can substantially influence observed associations. Int. J. Epidemiol. 47, 226–235 (2018). - PubMed
Watanabe, Y. et al. An amyotrophic lateral sclerosis-associated mutant of C21ORF2 is stabilized by NEK1-mediated hyperphosphorylation and the inability to bind FBXO3. iScience 23, 101491 (2020). - PubMed
Wood, A. R. et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46, 1173–1186 (2014). - PubMed
Luo, Y. et al. Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7. Nat. Genet. 49, 186–192 (2017). - PubMed
Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008). - PubMed
Saez-Atienzar, S. et al. Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types. Sci. Adv. 7, eabd9036 (2021). - PubMed
Yamanaka, K. et al. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl Acad. Sci. USA 105, 7594–7599 (2008). - PubMed
Ralph, G. S. et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat. Med. 11, 429–433 (2005). - PubMed
Blokhuis, A. M., Groen, E. J. N., Koppers, M., van den Berg, L. H. & Pasterkamp, R. J. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 125, 777–794 (2013). - PubMed
Seelen, M. et al. Prior medical conditions and the risk of amyotrophic lateral sclerosis. J. Neurol. 261, 1949–1956 (2014). - PubMed
Bandres-Ciga, S. et al. Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis. Ann. Neurol. 85, 470–481 (2019). - PubMed
Armon, C. Smoking is a cause of ALS. High LDL-cholesterol levels? Unsure. Ann. Neurol. 85, 465–469 (2019). - PubMed
Turner, M. R., Wotton, C., Talbot, K. & Goldacre, M. J. Cardiovascular fitness as a risk factor for amyotrophic lateral sclerosis: indirect evidence from record linkage study. J. Neurol. Neurosurg. Psychiatry 83, 395–398 (2012). - PubMed
Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009). - PubMed
Koga, H., Kaushik, S. & Cuervo, A. M. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 24, 3052–3065 (2010). - PubMed
Fraldi, A. et al. Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. EMBO J. 29, 3607–3620 (2010). - PubMed
Barbero-Camps, E. et al. Cholesterol impairs autophagy-mediated clearance of amyloid β while promoting its secretion. Autophagy 14, 1129–1154 (2018). - PubMed
Brooks, B. R., Miller, R. G., Swash, M. & Munsat, T. L. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 1, 293–299 (2000). - PubMed
Zhou, W. et al. Efficiently controlling for case–control imbalance and sample relatedness in large-scale genetic association studies. Nat. Genet. 50, 1335–1341 (2018). - PubMed
Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010). - PubMed
Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015). - PubMed
Brown, B. C. et al. Transethnic genetic-correlation estimates from summary statistics. Am. J. Hum. Genet. 99, 76–88 (2016). - PubMed
Yang, J. et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012). - PubMed
Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011). - PubMed
Project MinE ALS Sequencing Consortium. Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis. Eur. J. Hum. Genet. 26, 1537–1546 (2018). - PubMed
Spek, R. A. Avander. et al. The project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public. Amyotroph. Lateral Scler. Frontotemporal Degener. 20, 432–440 (2019). - PubMed
Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016). - PubMed
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff. Fly 6, 80–92 (2012). - PubMed
Vaser, R., Adusumalli, S., Leng, S. N., Sikic, M. & Ng, P. C. SIFT missense predictions for genomes. Nat. Protoc. 11, 1–9 (2016). - PubMed
Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010). - PubMed
Chun, S. & Fay, J. C. Identification of deleterious mutations within three human genomes. Genome Res. 19, 1553–1561 (2009). - PubMed
Schwarz, J. M., Cooper, D. N., Schuelke, M. & Seelow, D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat. Methods 11, 361–362 (2014). - PubMed
Reva, B., Antipin, Y. & Sander, C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 39, e118 (2011). - PubMed
Choi, Y. & Chan, A. P. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31, 2745–2747 (2015). - PubMed
Dolzhenko, E. et al. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res. 27, 1895–1903 (2017). - PubMed
Dolzhenko, E. et al. ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data. Genome Biol. 21, 102 (2020). - PubMed
Mousavi, N., Shleizer-Burko, S., Yanicky, R. & Gymrek, M. Profiling the genome-wide landscape of tandem repeat expansions. Nucleic Acids Res. 47, e90 (2019). - PubMed
Wu, Y. et al. Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits. Nat. Commun. 9, 918 (2018). - PubMed
Zhu, Z. et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat. Genet. 48, 481–487 (2016). - PubMed
Barbeira, A. N. et al. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat. Commun. 9, 1825 (2018). - PubMed
Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48, 245–252 (2016). - PubMed
Hannon, E. et al. Leveraging DNA-methylation quantitative-trait loci to characterize the relationship between methylomic variation, gene expression, and complex traits. Am. J. Hum. Genet. 103, 654–665 (2018). - PubMed
Hop, P. J. et al. Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference. Genome Biol. 21, 220 (2020). - PubMed
McLean, C. Y. et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501 (2010). - PubMed
Wei, T. et al. CpGtools: a Python package for DNA methylation analysis. Bioinformatics 37, 1598–1599 (2021). - PubMed
Zeng, J. et al. Signatures of negative selection in the genetic architecture of human complex traits. Nat. Genet. 50, 746–753 (2018). - PubMed
Lloyd-Jones, L. R. et al. Improved polygenic prediction by Bayesian multiple regression on summary statistics. Nat. Commun. 10, 5086 (2019). - PubMed
Kunkle, B. W. et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 51, 414–430 (2019). - PubMed
Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019). - PubMed
Ferrari, R., Hernandez, D. G., Nalls, M. A. & Rohrer, J. D. Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol. 13, 686–699 (2014). - PubMed
Kouri, N. et al. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat. Commun. 6, 7247 (2015). - PubMed
Marioni, R. E. et al. GWAS on family history of Alzheimer’s disease. Transl. Psychiatry 8, 99 (2018). - PubMed
International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019). - PubMed
Malik, R. et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat. Genet. 50, 524–537 (2018). - PubMed
Woo, D. et al. Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. Am. J. Hum. Genet. 94, 511–521 (2014). - PubMed
Bakker, M. K. et al. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nat. Genet. 52, 1303–1313 (2020). - PubMed
Watson, H. J. et al. Genome-wide association study identifies eight risk loci and implicates metabo–psychiatric origins for anorexia nervosa. Nat. Genet. 51, 1207–1214 (2019). - PubMed
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS). Revealing the complex genetic architecture of obsessive–compulsive disorder using meta-analysis. Mol. Psychiatry 23, 1181–1188 (2018). - PubMed
Otowa, T. et al. Meta-analysis of genome-wide association studies of anxiety disorders. Mol. Psychiatry 21, 1391–1399 (2016). - PubMed
Nievergelt, C. M. et al. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nat. Commun. 10, 4558 (2019). - PubMed
Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681 (2018). - PubMed
Stahl, E. A. et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat. Genet. 51, 793–803 (2019). - PubMed
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). - PubMed
Yu, D. et al. Interrogating the genetic determinants of Tourette’s syndrome and other tic disorders through genome-wide association studies. Am. J. Psychiatry 176, 217–227 (2019). - PubMed
Grove, J. et al. Identification of common genetic risk variants for autism spectrum disorder. Nat. Genet. 51, 431–444 (2019). - PubMed
Demontis, D. et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat. Genet. 51, 63–75 (2019). - PubMed
Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014). - PubMed
Darmanis, S. et al. A survey of human brain transcriptome diversity at the single cell level. Proc. Natl Acad. Sci. USA 112, 7285–7290 (2015). - PubMed
Hodge, R. D. et al. Conserved cell types with divergent features in human versus mouse cortex. Nature 573, 61–68 (2019). - PubMed
Saunders, A. et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015–1030 (2018). - PubMed
Lamparter, D., Marbach, D., Rueedi, R., Kutalik, Z. & Bergmann, S. Fast and rigorous computation of gene and pathway scores from SNP-based summary statistics. PLoS Comput. Biol. 12, e1004714 (2016). - PubMed
1000 Genomes Project Consortium et al. A global reference for human genetic variation. Nature 526, 68–74 (2015). - PubMed
Yengo, L. et al. Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry. Hum. Mol. Genet. 27, 3641–3649 (2018). - PubMed
Lee, J. J. et al. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat. Genet. 50, 1112–1121 (2018). - PubMed
Liu, M. et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat. Genet. 51, 237–244 (2019). - PubMed
Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015). - PubMed
van der Harst, P. & Verweij, N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ. Res. 122, 433–443 (2018). - PubMed
Evangelou, E. et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat. Genet. 50, 1412–1425 (2018). - PubMed
Vuckovic, D. et al. The polygenic and monogenic basis of blood traits and diseases. Cell 182, 1214–1231 (2020). - PubMed
Ligthart, S. et al. Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. Am. J. Hum. Genet. 103, 691–706 (2018). - PubMed
Willer, C. J. et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013). - PubMed
Zeng, P., Wang, T., Zheng, J. & Zhou, X. Causal association of type 2 diabetes with amyotrophic lateral sclerosis: new evidence from Mendelian randomization using GWAS summary statistics. BMC Med. 17, 225 (2019). - PubMed
Cragg, J. G. & Donald, S. G. Testing identifiability and specification in instrumental variable models. Econ. Theory 9, 222–240 (1993). - PubMed
Hemani, G. et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife 7, e34408 (2018). - PubMed
Smith, G. D., Davey Smith, G. & Hemani, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet. 23, R89–R98 (2014). - PubMed
Hemani, G., Tilling, K. & Davey Smith, G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 13, e1007081 (2017). - PubMed
Burgess, S. & Thompson, S. G. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am. J. Epidemiol. 181, 251–260 (2015). - PubMed
Sanderson, E., Davey Smith, G., Windmeijer, F. & Bowden, J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int. J. Epidemiol. 48, 713–727 (2019). - PubMed

Publication Types

Journal Article

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Affiliations

Abstract

References

Publication Types

Grant support