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| Home > Articles > Published articles > Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology |
| Home > Articles > Published articles > Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology |
(Utrecht University) (Utrecht University) (University Medical Centre Groningen) (University Medical Centre Groningen) (Utrecht University) (University of Exeter) (Utrecht University) (Utrecht University) (Trinity College Dublin) (King's College London) (King's College London) (Università degli Studi di Milano) (Universidade de Lisboa) (Queen's University Belfast) (University College London) (University Hospital Würzburg) (Humboldt University) (King's College London) (IRCCS Mondino Foundation) (University of Brescia) (Azienda Ospedaliero Universitaria Città della Salute e della Scienza) (Azienda Ospedaliero Universitaria Città della Salute e della Scienza) (Azienda Ospedaliero Universitaria Città della Salute e della Scienza.) (University of Bari at 'Pia Fondazione Card G) (Umeå University) (Hadassah Medical Center) (ICM, Sorbonne Université) (Hospital Universitari de Bellvitge) (Institut d'Investigació Biomèdica Sant Pau) (McGill University) (Hôpital de la Pitié Salpêtrière.) (UCL Institute of Neurology (Regne Unit)) (King's College London) (Christian Albrechts-University Kiel) (Christian Albrechts-University Kiel) (Kiel University) (Charité - Universitätsmedizin Berlin) (Charité - Universitätsmedizin Berlin) (Charité - Universitätsmedizin Berlin) (QIMR Berghofer Medical Research Institute (Brisbane, Austràlia)) (QIMR Berghofer Medical Research Institute (Brisbane, Austràlia)) (Erasmus Medical Center Rotterdam) (Heidelberg University. Central Institute of Mental Health) (Institute of Neuroscience and Medicine INM-1, Research Center Juelich) (University of Bonn. Life and Brain Center) (University of Lille) (University of Malta) (University of Pennsylvania) (University of Luebeck) (Jena University Hospital (Alemanya)) (Karolinska University Hospital and Karolinska Institutet (Suècia)) (Institute of Higher Nervous Activity and Neurophysiology Russian Academy of Sciences) (University of Ljubljana) (University Medical Centre Ljubljana.) (Calvary Health Care Bethlehem) (Murdoch University) (University of Queensland) (University of Sydney) (Macquarie University) (Macquarie University) (Neuroscience Research Australia Institute) (Neuropsychiatric Institute) (Universidade de Lisboa) (Hannover Medical School) (McGill University) (Università degli Studi di Milano) (King's College London.) (Emory University School of Medicine) (University of Massachusetts Medical School) (University of Massachusetts Medical School) (Umeå University) (Utrecht University) (Utrecht University) (Utrecht University) (Bristol Medical School) (Bristol Medical School) (Illumina) (University of Exeter) (Trinity College Dublin) (Trinity College Dublin) (University of Queensland) (Biogen) (University Medical Centre Groningen) (King's College Hospital NHS Foundation Trust) (University Hospitals Leuven (Bèlgica)) (Utrecht University)| Date: | 2021 |
| 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. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Motor neuron disease ; Genome-wide association studies ; Neurodegenerative diseases |
| Published in: | Nature genetics, Vol. 53 (december 2021) , p. 1636-1648, ISSN 1546-1718 |
