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Cited by 542Amyotrophic Lateral Sclerosis ResearchGenetic Associations and EpidemiologyMultiple Sclerosis Research Studies

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

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van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan +278 more·2021·Nature Genetics
DOI 10.1038/s41588-021-00973-1PMC PMC8648564

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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.

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  • The observation of distinct tissue enrichment for MS severity versus susceptibility is unique to MS.

    “Although divergent genetic determinants of susceptibility and progression have been noted in other conditions8,9,36, the observation of distinct tissue enrichment is to our knowledge unique to MS.”

    From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [36]

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van Rheenen, W., van der Spek, R. A. A., Bakker, M. K., van Vugt, J. J. F. A., Hop, P. J., Zwamborn, R. A. J., de Klein, N., Westra, H.-J., Bakker, O. B., Deelen, P., Shireby, G., Hannon, E., Moisse, M., Baird, D., Restuadi, R., Dolzhenko, E., Dekker, A. M., Gawor, K., Westeneng, H.-J., Tazelaar, G. H. P., van Eijk, K. R., Kooyman, M., Byrne, R. P., Doherty, M., Heverin, M., Al Khleifat, A., Iacoangeli, A., Shatunov, A., Ticozzi, N., Cooper-Knock, J., Smith, B. N., Gromicho, M., Chandran, S., Pal, S., Morrison, K. E., Shaw, P. J., Hardy, J., Orrell, R. W., Sendtner, M., Meyer, T., Başak, N., van der Kooi, A. J., Ratti, A., Fogh, I., Gellera, C., Lauria, G., Corti, S., Cereda, C., Sproviero, D., D’Alfonso, S., Sorarù, G., Siciliano, G., Filosto, M., Padovani, A., Chiò, A., Calvo, A., Moglia, C., Brunetti, M., Canosa, A., Grassano, M., Beghi, E., Pupillo, E., Logroscino, G., Nefussy, B., Osmanovic, A., Nordin, A., Lerner, Y., Zabari, M., Gotkine, M., Baloh, R. H., Bell, S., Vourc’h, P., Corcia, P., Couratier, P., Millecamps, S., Meininger, V., Salachas, F., Mora Pardina, J. S., Assialioui, A., Rojas-García, R., Dion, P. A., Ross, J. P., Ludolph, A. C., Weishaupt, J. H., Brenner, D., Freischmidt, A., Bensimon, G., Brice, A., Durr, A., Payan, C. A. M., Saker-Delye, S., Wood, N. W., Topp, S., Rademakers, R., Tittmann, L., Lieb, W., Franke, A., Ripke, S., Braun, A., Kraft, J., Whiteman, D. C., Olsen, C. M., Uitterlinden, A. G., Hofman, A., Rietschel, M., Cichon, S., Nöthen, M. M., Amouyel, P., SLALOM Consortium, Comi, G., Riva, N., Lunetta, C., Gerardi, F., Cotelli, M. S., Rinaldi, F., Chiveri, L., Guaita, M. C., Perrone, P., Ceroni, M., Diamanti, L., Ferrarese, C., Tremolizzo, L., Delodovici, M. L., Bono, G., PARALS Consortium, Canosa, A., Manera, U., Vasta, R., Bombaci, A., Casale, F., Fuda, G., Salamone, P., Iazzolino, B., Peotta, L., Cugnasco, P., De Marco, G., Torrieri, M. C., Palumbo, F., Gallone, S., Barberis, M., Sbaiz, L., Gentile, S., Mauro, A., Mazzini, L., De Marchi, F., Corrado, L., D’Alfonso, S., Bertolotto, A., Gionco, M., Leotta, D., Odddenino, E., Imperiale, D., Cavallo, R., Pignatta, P., De Mattei, M., Geda, C., Papurello, D. M., Gusmaroli, G., Comi, C., Labate, C., Ruiz, L., Ferrandi, D., Rota, E., Aguggia, M., Di Vito, N., Meineri, P., Ghiglione, P., Launaro, N., Dotta, M., Di Sapio, A., Giardini, G., SLAGEN Consortium, Tiloca, C., Peverelli, S., Taroni, F., Pensato, V., Castellotti, B., Comi, G. P., Del Bo, R., Ceroni, M., Gagliardi, S., Corrado, L., Mazzini, L., Raggi, F., Simoncini, C., Lo Gerfo, A., Inghilleri, M., Ferlini, A., SLAP Consortium, Simone, I. L., Passarella, B., Guerra, V., Zoccolella, S., Nozzoli, C., Mundi, C., Leone, M., Zarrelli, M., Tamma, F., Valluzzi, F., Calabrese, G., Boero, G., Rini, A., Traynor, B. J., Singleton, A. B., Mitne Neto, M., Cauchi, R. J., Ophoff, R. A., Wiedau-Pazos, M., Lomen-Hoerth, C., van Deerlin, V. M., Grosskreutz, J., Roediger, A., Gaur, N., Jörk, A., Barthel, T., Theele, E., Ilse, B., Stubendorff, B., Witte, O. W., Steinbach, R., Hübner, C. A., Graff, C., Brylev, L., Fominykh, V., Demeshonok, V., Ataulina, A., Rogelj, B., Koritnik, B., Zidar, J., Ravnik-Glavač, M., Glavač, D., Stević, Z., Drory, V., Povedano, M., Blair, I. P., Kiernan, M. C., Benyamin, B., Henderson, R. D., Furlong, S., Mathers, S., McCombe, P. A., Needham, M., Ngo, S. T., Nicholson, G. A., Pamphlett, R., Rowe, D. B., Steyn, F. J., Williams, K. L., Mather, K. A., Sachdev, P. S., Henders, A. K., Wallace, L., de Carvalho, M., Pinto, S., Petri, S., Weber, M., Rouleau, G. A., Silani, V., Curtis, C. J., Breen, G., Glass, J. D., Brown, R. H., Landers, J. E., Shaw, C. E., Andersen, P. M., Groen, E. J. N., van Es, M. A., Pasterkamp, R. J., Fan, D., Garton, F. C., McRae, A. F., Davey Smith, G., Gaunt, T. R., Eberle, M. A., Mill, J., McLaughlin, R. L., Hardiman, O., Kenna, K. P., Wray, N. R., Tsai, E., Runz, H., Franke, L., Al-Chalabi, A., Van Damme, P., van den Berg, L. H., & Veldink, J. H.
Affiliations
  • Utrecht University (NL)
  • University Medical Center Groningen (NL)
  • University of Exeter (GB)
  • Universitair Ziekenhuis Leuven (BE)
  • Biogen (United States) (US)
  • The University of Queensland (AU)
  • Illumina (United States) (US)
  • Trinity College Dublin (IE)
  • King's College London (GB)
  • University of Milan (IT)
  • University of Lisbon (PT)
  • UK Dementia Research Institute (GB)
  • Queen's University Belfast (GB)
  • University of Sheffield (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • Universitätsklinikum Würzburg (DE)
  • Humboldt-Universität zu Berlin (DE)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT)
  • University of Pisa (IT)
  • University of Brescia (IT)
  • Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
  • University of Turin (IT)
  • Mario Negri Institute for Pharmacological Research (IT)
  • University of Bari Aldo Moro (IT)
  • Tel Aviv Sourasky Medical Center (IL)
  • Medizinische Hochschule Hannover (DE)
  • Umeå University (SE)
  • Hebrew University of Jerusalem (IL)
  • Cedars-Sinai Medical Center (US)
  • Université de Tours (FR)
  • Inserm (FR)
  • Centre National de la Recherche Scientifique (FR)
  • Ramsay Santé Hôpital privé des Peupliers (FR)
  • Bellvitge University Hospital (ES)
  • Montreal Neurological Institute and Hospital (CA)
  • Universität Ulm (DE)
  • Heidelberg University (DE)
  • Sorbonne Université (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • National Hospital for Neurology and Neurosurgery (GB)
  • Mayo Clinic (US)
  • Christian-Albrechts-Universität zu Kiel (DE)
  • Broad Institute (US)
  • Charité – Universitätsmedizin Berlin (DE)
  • QIMR Berghofer Medical Research Institute (AU)
  • University of Bonn (DE)
  • IRCCS Ospedale San Raffaele (IT)
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
  • Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
  • Ospedale Valduce (IT)
  • Azienda Ospedaliera Ospedale Civile di Legnano (IT)
  • University of Milano-Bicocca (IT)
  • Ospedale di Circolo e Fondazione Macchi (IT)
  • IRCCS Istituto Auxologico Italiano (IT)
  • Ospedale San Luigi Gonzaga (IT)
  • A. O. Ordine Mauriziano di Torino (IT)
  • Ospedale Martini (IT)
  • Ospedale Maria Vittoria (IT)
  • Ospedale San Giovanni Bosco (IT)
  • Ospedale Humanitas Gradenigo (IT)
  • Ospedale Civile Di Ivrea (IT)
  • Ospedale degli Infermi (IT)
  • Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
  • Ospedale Civile Edoardo Agnelli (IT)
  • Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo (IT)
  • Azienda Sanitaria Locale Alessandria (IT)
  • Azienda Sanitaria Locale di Asti (IT)
  • Azienda Sanitaria Ospedaliera S.Croce e Carle Cuneo (IT)
  • Ospedale Michele e Pietro Ferrero - Verduno (IT)
  • Vita-Salute San Raffaele University (IT)
  • University of Padua (IT)
  • Sapienza University of Rome (IT)
  • University of Ferrara (IT)
  • Ospedale A. Perrino (IT)
  • Gastroenterology Hospital "Saverio de Bellis" (IT)
  • Ospedale San Paolo (IT)
  • Casa Sollievo della Sofferenza (IT)
  • Ospedale Generale Regionale Francesco Miulli (IT)
  • Ospedale Vito Fazzi (IT)
  • National Institutes of Health (US)
  • University of Malta (MT)
  • University of California, Los Angeles (US)
  • University Hospital Schleswig-Holstein (DE)
  • Jena University Hospital (DE)
  • Karolinska University Hospital (SE)
  • Russian Academy of Sciences (RU)
  • Moscow City Clinical Hospital after V.M. Buyanov (RU)
  • University of Ljubljana (SI)
  • Ljubljana University Medical Centre (SI)
  • University of Belgrade (RS)
  • Tel Aviv University (IL)
  • Macquarie University (AU)
  • The University of Sydney (AU)
  • Calvary Health Care Bethlehem (AU)
  • Murdoch University (AU)
  • Concord Repatriation General Hospital (AU)
  • UNSW Sydney (AU)
  • Kantonsspital St. Gallen (CH)
  • Emory University (US)
  • University of Massachusetts Chan Medical School (US)
  • Peking University (CN)
  • University of Bristol (GB)
Corresponding author
Veldink, Jan H.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-12
Volume
53
Issue
12
Pages
1636-1648
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-021-00973-1
PMC
PMC8648564
OpenAlex
W4226286160
Cited by
542
References
31
Citations by year
2026: 96 · 2025: 129 · 2024: 124 · 2023: 117 · 2022: 67 · 2021: 9
FWCI
38.12
Type
journal article
Language
en
Update notices
correction (2022-01-31)
Open access
Licence
Locations
  • Nature Genetics (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, other-oa)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Lirias (submittedVersion, other-oa)
  • Research Portal (Queen's University Belfast) (submittedVersion, cc-by)
  • Murdoch University Research Portal (submittedVersion)
  • UniSA Research Outputs Repository (University of South Australia) (submittedVersion, cc-by)
  • OAR@UM (University of Malta) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
  • DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
  • HAL (submittedVersion, cc-by)
  • BOA (University of Milano-Bicocca) (submittedVersion, cc-by)
  • Digital Collections portal (Koç University) (submittedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
  • DZNE Pub (submittedVersion, other-oa)
  • Explore Bristol Research (submittedVersion, cc-by)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
  • Biogen
  • South London and Maudsley NHS Foundation Trust (MR/R024804/1, MR/L501529/1, ES/L008238/1)
  • Wellcome Trust (MC_UU_00011/1, MC_UU_00011/4, 216596/Z/19/Z)
  • Health Research Board (JPI-JPND-2017-1)
  • EU Joint Programme – Neurodegenerative Disease Research (MR/R024804/1, MR/L501529/1)
  • Health~Holland
  • Alzheimer's Society
  • National Institute for Health and Care Research (ES/L008238/1, NF-SI-0617-10077, MR/L501529/1, MC_UU_00011/4, NF-SI-0512-10082, NIHR202421, MR/R024804/1, MC_UU_00011/1)
  • Parkinson's UK (G-0907, G-1307)
  • Motor Neurone Disease Association (ALCHALABI-TALBOT/APR14/926-794, 259867, 772376, ALCHALABI-DOBSON/APR14/829-791, Smith/Apr16/847-791, MR/L501529/1, Al-Chalabi/Apr19/870-791, Shaw/Apr15/970-797, Shaw/Nov14/985-797, ES/L008238/1, MR/R024804/1)
  • King's College London
  • European Commission (HORIZON2020, MC_UU_00011/1, 772376, 259867)
  • Rosetrees Trust
  • University of Bristol (MC_UU_00011/4, MC_UU_00011/1)
  • Agence Nationale de la Recherche (ANR-11-LABX-0009, ANR-17-JPCD-0001)
  • Fonds Wetenschappelijk Onderzoek
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (09150161810018)
  • KU Leuven
  • Prinses Beatrix Spierfonds (W.OR20-08, W.F19-03)
  • Vlaamse regering
  • Stichting ALS Nederland (140935)
  • NIHR Maudsley Biomedical Research Centre (ES/L008238/1, MR/R024804/1, MR/L501529/1)
  • Canadian Institutes of Health Research (FRN159279, 140935)
  • Medical Research Council (MR/L023784/2, 259867, MR/K01417X/1, ES/L008238/1, MC_PC_17115, MC_UU_00011/4, 350833, MR/L501542/1, MR/L021803/1, 1113400, MC_G1000733, MR/J004758/1, MR/R024804/1, MR/L501529/1, 1078901, K013807, MC_UU_00011/1, M008924, MC_UU_00011/1 and MC_UU_00011/4, MC_UU_00011)
  • Economic and Social Research Council (ES/L008238/1, MC_UU_00011/1, L008238, 1095215, MR/L501529/1, MR/R024804/1)
  • National Health and Medical Research Council (568969, 1063061, 1155413, 1095215, 1079102, 401162, 1113400, 1078901, 1083187, 1093083, 1173790, 1121962, 1085606, MC_UU_00011/1, 1025243, MC_UU_00011/4, 1024224, 402703, 1073898, 1045325, 350833, 1185416)
  • National Institute of Neurological Disorders and Stroke (K08NS002240, R01NS073873, R56NS073873, P01NS049134)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
amyotrophic lateral sclerosis, genetic susceptibility loci, rare variants, microsatellite markers, genetic architecture, neurodegenerative diseases, cholesterol, Mendelian randomization, vesicle trafficking, autophagy, glutamatergic neurons, expression quantitative trait loci
MeSH terms
RNA-Seq, Amyotrophic Lateral Sclerosis, Brain, Cholesterol, Female, Glutamine, Humans, Male, Mutation, Neurons, Risk Factors, Disease Progression, Microsatellite Repeats, Neurodegenerative Diseases, Quantitative Trait Loci, Genome-Wide Association Study, Mendelian Randomization Analysis

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