Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Wouter van Rheenen(Utrecht University), Rick A. A. van der Spek(Utrecht University), Mark K. Bakker(Utrecht University), Joke J.F.A. van Vugt(Utrecht University), Paul J. Hop(Utrecht University), Ramona A.J. Zwamborn(Utrecht University), Niek de Klein(University Medical Center Groningen), Harm-Jan Westra(University Medical Center Groningen), Olivier B. Bakker(University Medical Center Groningen), Patrick Deelen(University Medical Center Groningen), Gemma Shireby(University of Exeter), Eilís Hannon(University of Exeter), Matthieu Moisse(VIB-KU Leuven Center for Brain & Disease Research), Denis Baird(Biogen (United States)), Restuadi Restuadi(The University of Queensland), Egor Dolzhenko(Illumina (United States)), Annelot M. Dekker(Utrecht University), Klara Gawor(Utrecht University), Henk‐Jan Westeneng(Utrecht University), Gijs H.P. Tazelaar(Utrecht University), Kristel R. van Eijk(Utrecht University), Maarten Kooyman(Utrecht University), Ross P. Byrne(Trinity College Dublin), Mark A. Doherty(Trinity College Dublin), Mark Heverin(Trinity College Dublin), Ahmad Al Khleifat(King's College London), Alfredo Iacoangeli(King's College London), Aleksey Shatunov(King's College London), Nicola Ticozzi(University of Milan), Johnathan Cooper‐Knock(University of Sheffield), Bradley Smith(King's College London), Marta Gromicho(University of Lisbon), Siddharthan Chandran(Mott MacDonald (United Kingdom)), Suvankar Pal(Mott MacDonald (United Kingdom)), Karen Morrison(Queen's University Belfast), Pamela J. Shaw(University of Sheffield), John Hardy(University College London), Richard W. Orrell(National Hospital for Neurology and Neurosurgery), Michael Sendtner(Universitätsklinikum Würzburg), Thomas Meyer(Humboldt-Universität zu Berlin), Nazlı Başak(Koç University), Anneke J. van der Kooi(Amsterdam UMC Location University of Amsterdam), Antonia Ratti(University of Milan), Isabella Fogh(King's College London), Cinzia Gellera(Fondazione IRCCS Istituto Neurologico Carlo Besta), Giuseppe Lauria(University of Milan), Stefania Corti(University of Milan), Cristina Cereda(Center for Genomic Science), Daisy Sproviero(Center for Genomic Science), Sandra D’Alfonso(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Gianni Sorarú(University of Padua), Gabriele Siciliano(University of Pisa), Massimiliano Filosto(University of Brescia), Alessandro Padovani(University of Brescia), Adriano Chiò(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Andrea Calvo(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Cristina Moglia(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Maura Brunetti(University of Turin), Antonio Canosa(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Maurizio Grassano(University of Turin), Ettore Beghi(Mario Negri Institute for Pharmacological Research), Elisabetta Pupillo(Mario Negri Institute for Pharmacological Research), Giancarlo Logroscino(University of Bari Aldo Moro), Beatrice Nefussy(Tel Aviv Sourasky Medical Center), Alma Osmanovic(Medizinische Hochschule Hannover), Angelica Nordin(Umeå University), Yossef Lerner(Hebrew University of Jerusalem), Michal Zabari(Hebrew University of Jerusalem), Marc Gotkine(Hebrew University of Jerusalem), Robert H. Baloh(Cedars-Sinai Medical Center), Shaughn Bell(Cedars-Sinai Medical Center), Patrick Vourc’h(Centre Hospitalier Universitaire de Tours), Philippe Corcia(Université de Tours), Philippe Couratier(Inserm), Stéphanie Millecamps(Centre National de la Recherche Scientifique), Vincent Meininger(Générale de Santé), François Salachas(Centre National de la Recherche Scientifique), Jesús S. Mora Pardina(Hospital Universitario San Rafael), Abdelilah Assialioui(Bellvitge University Hospital), Ricardo Rojas-García(Universitat Autònoma de Barcelona), Patrick A. Dion(Montreal Neurological Institute and Hospital), Jay P. Ross(Montreal Neurological Institute and Hospital), Albert C. Ludolph(Universität Ulm), Jochen H. Weishaupt(Heidelberg University), Dávid Brenner(Heidelberg University), Axel Freischmidt(Universität Ulm), Gilbert Bensimon(Université Sorbonne Nouvelle), Alexis Brice(Centre National de la Recherche Scientifique), Alexandra Durr(Centre National de la Recherche Scientifique), C. Payán(Sorbonne Université), Safa Saker-Delye(Centre National de la Recherche Scientifique), Nicholas Wood(National Hospital for Neurology and Neurosurgery), Simon Topp(King's College London), Rosa Rademakers(Jacksonville College), Lukas Tittmann(Christian-Albrechts-Universität zu Kiel), Wolfgang Lieb(Christian-Albrechts-Universität zu Kiel), André Franke(Christian-Albrechts-Universität zu Kiel), Stephan Ripke(Broad Institute), Alice Braun(Charité - Universitätsmedizin Berlin), Julia Kraft(Charité - Universitätsmedizin Berlin), David C. Whiteman(QIMR Berghofer Medical Research Institute), Catherine M. Olsen(QIMR Berghofer Medical Research Institute), André G. Uitterlinden(Erasmus MC), Albert Hofman(Erasmus MC), Marcella Rietschel(Heidelberg University), Sven Cichon(University of Bonn), Markus M. Nöthen(University of Bonn), Philippe Amouyel(Inserm), Giancarlo Comi(Vita-Salute San Raffaele University), Nilo Riva(Vita-Salute San Raffaele University), Christian Lunetta(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Francesca Gerardi(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Maria Sofia Cotelli(University of Brescia), Fabrizio Rinaldi(Brescia University), Luca Chiveri(Ospedale Valduce), Maria Cristina Guaita(Azienda Ospedaliera Ospedale Civile di Legnano), Patrizia Perrone(Azienda Ospedaliera Ospedale Civile di Legnano), Mauro Ceroni(Fondazione Istituto Neurologico Nazionale Casimiro Mondino), Luca Diamanti(Fondazione Istituto Neurologico Nazionale Casimiro Mondino), Carlo Ferrarese(University of Milano-Bicocca), Lucio Tremolizzo(University of Milano-Bicocca), Maria Luisa DeLodovici(Ospedale di Circolo e Fondazione Macchi), Giorgio Bono(Ospedale di Circolo e Fondazione Macchi), Antonio Canosa(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Umberto Manera(University of Turin), Rosario Vasta(University of Turin), Alessandro Bombaci(University of Turin), Federico Casale(University of Turin), Giuseppe Fuda(University of Turin), Paolina Salamone(University of Turin), Barbara Iazzolino(University of Turin), Laura Peotta(University of Turin), Paolo Cugnasco(University of Turin), Giovanni De Marco(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Maria Claudia Torrieri(University of Turin), Francesca Palumbo(University of Turin), Salvatore Gallone(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Marco Barberis(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Luca Sbaiz(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Salvatore Gentile(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Alessandro Mauro(University of Turin), Letizia Mazzini(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Fabiola De Marchi(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Lucia Corrado(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Sandra D’Alfonso(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Antonio Bertolotto(Ospedale San Luigi Gonzaga), Maurizio Gionco(A. O. Ordine Mauriziano di Torino), Daniela Leotta(Ospedale Martini), Enrico Odddenino(Ospedale Martini), Daniele Imperiale(Ospedale Maria Vittoria), Roberto Cavallo(Ospedale San Giovanni Bosco), Pietro Pignatta(Ospedale Humanitas Gradenigo), Marco De Mattei, Claudio Geda(Ospedale Civile Di Ivrea), Diego Maria Papurello(Presidio Ospedaliero), Graziano Gusmaroli(Ospedale degli Infermi), Cristoforo Comi(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Carmelo Labate(Ospedale Civile Edoardo Agnelli), Luigi Ruiz, Delfina Ferrandi(Azienda Sanitaria Locale Alessandria), Eugenia Rota(Ospedale San Giacomo Apostolo), Marco Aguggia(Azienda Sanitaria Locale di Asti), Nicoletta Di Vito(Azienda Sanitaria Locale di Asti), P. Meineri(Azienda Sanitaria Ospedaliera S.Croce e Carle Cuneo), Paolo Ghiglione(Ospedale Maggiore), Nicola Launaro(Ospedale Maggiore), Michele Dotta(Ospedale San Pietro Fatebenefratelli), Alessia Di Sapio(Ospedale Regina Margherita), Guido Giardini, Cinzia Tiloca(IRCCS Istituto Auxologico Italiano), Silvia Peverelli(IRCCS Istituto Auxologico Italiano), Franco Taroni(Fondazione IRCCS Istituto Neurologico Carlo Besta), Viviana Pensato(Fondazione IRCCS Istituto Neurologico Carlo Besta), Barbara Castellotti(Fondazione IRCCS Istituto Neurologico Carlo Besta), Giacomo P. Comi(Vita-Salute San Raffaele University), Roberto Del Bo(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Mauro Ceroni(Fondazione Istituto Neurologico Nazionale Casimiro Mondino), Stella Gagliardi(Center for Genomic Science), Lucia Corrado(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Letizia Mazzini(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Flavia Raggi(University of Padua), Costanza Simoncini(University of Pisa), Annalisa Lo Gerfo(University of Pisa), Maurizio Inghilleri(Sapienza University of Rome), Alessandra Ferlini(University of Ferrara), Isabella L. Simone(University of Bari Aldo Moro), Bruno Passarella(Ospedale A. Perrino), Vito Guerra(Gastroenterology Hospital "Saverio de Bellis"), Stefano Zoccolella(Ospedale San Paolo), Cecilia Nozzoli(Ospedale A. Perrino), Ciro Mundi(University of Foggia), Maurizio Leone(Casa Sollievo della Sofferenza), Michele Zarrelli(Casa Sollievo della Sofferenza), Filippo Tamma, Francesco Valluzzi(Ospedale San Giacomo Apostolo), Gianluigi Calabrese(Ospedale Vito Fazzi), Giovanni Boero(Ospedale SS. Annunziata), Augusto Rini(Ospedale A. Perrino), Bryan J. Traynor(Johns Hopkins University), Andrew Singleton(National Institute on Aging), Miguel Mitne Neto(Universidade de São Paulo), Ruben J. Cauchi(University of Malta), Roel A. Ophoff(University of California, Los Angeles), Martina Wiedau‐Pazos(University of California, Los Angeles), Catherine Lomen-Hoerth(University of California, San Francisco), Vivianna M. Van Deerlin(University of Pennsylvania), Julian Großkreutz(University Hospital Schleswig-Holstein), Annekathrin Roediger(Jena University Hospital), Nayana Gaur(Jena University Hospital), Alexander Jörk(Jena University Hospital), Tabea Barthel(Jena University Hospital), Erik Theele(Jena University Hospital), Benjamin Ilse(Jena University Hospital), Beatrice Stubendorff(Jena University Hospital), Otto W. Witte(Jena University Hospital), Robert Steinbach(Jena University Hospital), Christian A. Hübner(Jena University Hospital), Caroline Graff(Karolinska University Hospital), Lev Brylev(Moscow Research and Clinical Center for Neuropsychiatry), Vera Fominykh(Institute of Higher Nervous Activity and Neurophysiology), Vera Demeshonok, Anastasia Ataulina, Boris Rogelj(University of Ljubljana), Blaž Koritnik(Ljubljana University Medical Centre), Janez Zidar(Ljubljana University Medical Centre), Metka Ravnik-Glavač(University of Ljubljana), Damjan Glavač(University of Ljubljana), Zorica Stević(University of Belgrade), Vivian Drory(Tel Aviv University), Mónica Povedano(Bellvitge University Hospital), Ian P. Blair(Macquarie University), Matthew C. Kiernan(The University of Sydney), Beben Benyamin(The University of Queensland), Robert D. Henderson(The University of Queensland), Sarah Furlong(Macquarie University), Susan Mathers(Calvary Health Care Bethlehem), Pamela McCombe(The University of Queensland), Merrilee Needham(Murdoch University), Shyuan T. Ngo(The University of Queensland), Garth A. Nicholson(Concord Repatriation General Hospital), Roger Pamphlett(The University of Sydney), Dominic B. Rowe(Macquarie University), Frederik J. Steyn(The University of Queensland), Kelly L. Williams(Macquarie University), Karen A. Mather(UNSW Sydney), Perminder S. Sachdev(UNSW Sydney), Anjali K. Henders(The University of Queensland), Leanne Wallace(The University of Queensland), Mamede de Carvalho(University of Lisbon), Susana Pinto(University of Lisbon), Susanne Petri(Medizinische Hochschule Hannover), Markus Weber(Kantonsspital St. Gallen), Guy A. Rouleau(Montreal Neurological Institute and Hospital), Vincenzo Silani(University of Milan), Charles Curtis(King's College London), Gerome Breen(King's College London), Jonathan D. Glass(Emory University), Robert H. Brown(University of Massachusetts Chan Medical School), John E. Landers(University of Massachusetts Chan Medical School), Christopher E. Shaw(King's College London), Peter M. Andersen(Umeå University), Ewout J. N. Groen(Utrecht University), Michael A. van Es(Utrecht University), R. Jeroen Pasterkamp(Utrecht University), Dongsheng Fan(Peking University), Fleur C. Garton(The University of Queensland), Allan F. McRae(The University of Queensland), George Davey Smith(At Bristol), Tom R. Gaunt(At Bristol), Michael A. Eberle(Illumina (United States)), Jonathan Mill(University of Exeter), Russell L. McLaughlin(Trinity College Dublin), Orla Hardiman(Trinity College Dublin), Kevin P. Kenna(Utrecht University), Naomi R. Wray(The University of Queensland), Ellen Tsai(Biogen (United States)), Heiko Runz(Biogen (United States)), Lude Franke(University Medical Center Groningen), Ammar Al‐Chalabi(King's College London), Philip Van Damme(VIB-KU Leuven Center for Brain & Disease Research), Leonard H. van den Berg(Utrecht University), Jan H. Veldink(Utrecht University)
Cited by 540Open Access
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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