Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Authors: 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 , Bakker Olivier B. , Deelen Patrick , Shireby Gemma , Hannon Eilis , Moisse Matthieu , Baird Denis , Restuadi Restuadi , Dolzhenko Egor , Dekker Annelot M. , Gawor Klara , Westeneng Henk-Jan , Tazelaar Gijs H. P. , van Eijk Kristel R. , Kooyman Maarten , Byrne Ross P. , Doherty Mark , Heverin Mark , Al Khleifat Ahmad , Iacoangeli Alfredo , Shatunov Aleksey , Ticozzi Nicola , Cooper-Knock Johnathan , Smith Bradley N. , Gromicho Marta , Chandran Siddharthan , Pal Suvankar , Morrison Karen E. , Shaw Pamela J. , Hardy John , Orrell Richard W. , Sendtner Michael , Meyer Thomas , Başak Nazli , van der Kooi Anneke J. , Ratti Antonia , Fogh Isabella , Gellera Cinzia , Lauria Giuseppe , Corti Stefania , Cereda Cristina , Sproviero Daisy , D’Alfonso Sandra , Sorarù Gianni , Siciliano Gabriele , Filosto Massimiliano , Padovani Alessandro , Chiò Adriano , Calvo Andrea , Moglia Cristina , Brunetti Maura , Canosa Antonio , Grassano Maurizio , Beghi Ettore , Pupillo Elisabetta , Logroscino Giancarlo , Nefussy Beatrice , Osmanovic Alma , Nordin Angelica , Lerner Yossef , Zabari Michal , Gotkine Marc , Baloh Robert H. , Bell Shaughn , Vourc’h Patrick , Corcia Philippe , Couratier Philippe , Millecamps Stéphanie , Meininger Vincent , Salachas François , Mora Pardina Jesus S. , Assialioui Abdelilah , Rojas-García Ricardo , Dion Patrick A. , Ross Jay P. , Ludolph Albert C. , Weishaupt Jochen H. , Brenner David , Freischmidt Axel , Bensimon Gilbert , Brice Alexis , Durr Alexandra , Payan Christine A. M. , Saker-Delye Safa , Wood Nicholas W. , Topp Simon , Rademakers Rosa , Tittmann Lukas , Lieb Wolfgang , Franke Andre , Ripke Stephan , Braun Alice , Kraft Julia , Whiteman David C. , Olsen Catherine M. , Uitterlinden Andre G. , Hofman Albert , Rietschel Marcella , Cichon Sven , Nöthen Markus M. , Amouyel Philippe ,   SLALOM Consortium, Comi Giancarlo , Riva Nilo , Lunetta Christian , Gerardi Francesca , Cotelli Maria Sofia , Rinaldi Fabrizio , Chiveri Luca , Guaita Maria Cristina , Perrone Patrizia , Ceroni Mauro , Diamanti Luca , Ferrarese Carlo , Tremolizzo Lucio , Delodovici Maria Luisa , Bono Giorgio ,   PARALS Consortium, Canosa Antonio , Manera Umberto , Vasta Rosario , Bombaci Alessandro , Casale Federico , Fuda Giuseppe , Salamone Paolina , Iazzolino Barbara , Peotta Laura , Cugnasco Paolo , De Marco Giovanni , Torrieri Maria Claudia , Palumbo Francesca , Gallone Salvatore , Barberis Marco , Sbaiz Luca , Gentile Salvatore , Mauro Alessandro , Mazzini Letizia , De Marchi Fabiola , Corrado Lucia , D’Alfonso Sandra , Bertolotto Antonio , Gionco Maurizio , Leotta Daniela , Odddenino Enrico , Imperiale Daniele , Cavallo Roberto , Pignatta Pietro , De Mattei Marco , Geda Claudio , Papurello Diego Maria , Gusmaroli Graziano , Comi Cristoforo , Labate Carmelo , Ruiz Luigi , Ferrandi Delfina , Rota Eugenia , Aguggia Marco , Di Vito Nicoletta , Meineri Piero , Ghiglione Paolo , Launaro Nicola , Dotta Michele , Di Sapio Alessia , Giardini Guido ,   SLAGEN Consortium, Tiloca Cinzia , Peverelli Silvia , Taroni Franco , Pensato Viviana , Castellotti Barbara , Comi Giacomo P. , Del Bo Roberto , Ceroni Mauro , Gagliardi Stella , Corrado Lucia , Mazzini Letizia , Raggi Flavia , Simoncini Costanza , Lo Gerfo Annalisa , Inghilleri Maurizio , Ferlini Alessandra ,   SLAP Consortium, Simone Isabella L. , Passarella Bruno , Guerra Vito , Zoccolella Stefano , Nozzoli Cecilia , Mundi Ciro , Leone Maurizio , Zarrelli Michele , Tamma Filippo , Valluzzi Francesco , Calabrese Gianluigi , Boero Giovanni , Rini Augusto , Traynor Bryan J. , Singleton Andrew B. , Mitne Neto Miguel , Cauchi Ruben J. , Ophoff Roel A. , Wiedau-Pazos Martina , Lomen-Hoerth Catherine , van Deerlin Vivianna M. , Grosskreutz Julian , Roediger Annekathrin , Gaur Nayana , Jörk Alexander , Barthel Tabea , Theele Erik , Ilse Benjamin , Stubendorff Beatrice , Witte Otto W. , Steinbach Robert , Hübner Christian A. , Graff Caroline , Brylev Lev , Fominykh Vera , Demeshonok Vera , Ataulina Anastasia , Rogelj Boris , Koritnik Blaž , Zidar Janez , Ravnik-Glavač Metka , Glavač Damjan , Stević Zorica , Drory Vivian , Povedano Monica , Blair Ian P. , Kiernan Matthew C. , Benyamin Beben , Henderson Robert D. , Furlong Sarah , Mathers Susan , McCombe Pamela A. , Needham Merrilee , Ngo Shyuan T. , Nicholson Garth A. , Pamphlett Roger , Rowe Dominic B. , Steyn Frederik J. , Williams Kelly L. , Mather Karen A. , Sachdev Perminder S. , Henders Anjali K. , Wallace Leanne , de Carvalho Mamede , Pinto Susana , Petri Susanne , Weber Markus , Rouleau Guy A. , Silani Vincenzo , Curtis Charles J. , Breen Gerome , Glass Jonathan D. , Brown Robert H. , Landers John E. , Shaw Christopher E. , Andersen Peter M. , Groen Ewout J. N. , van Es Michael A. , Pasterkamp R. Jeroen , Fan Dongsheng , Garton Fleur C. , McRae Allan F. , Davey Smith George , Gaunt Tom R. , Eberle Michael A. , Mill Jonathan , McLaughlin Russell L. , Hardiman Orla , Kenna Kevin P. , Wray Naomi R. , Tsai Ellen , Runz Heiko , Franke Lude , Al-Chalabi Ammar , Van Damme Philip , van den Berg Leonard H. , Veldink Jan H. 
Published: December 2021

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.