Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Authors: Rheenen Wouter van , van der Spek Rick A.A. , Bakker Mark K. , Vugt Joke J.F.A. van , Hop Paul J. , Zwamborn Ramona A.J. , Klein Niek de , 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 , Khleifat Ahmad Al , 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 Pinter 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 , Pardina Jesus S. Mora , Assialioui Abdelilah , Rojas-García Ricardo , Dion Patrick , Ross Jay P. , Ludolph Albert C. , Weishaupt Jochen H. , Brenner David , Freischmidt Axel , Bensimon Gilbert , Brice Alexis , Dürr Alexandra , Payan Christine A.M. , Saker-Delye Safa , Wood Nicholas , 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,   PARALS Consortium,   SLAGEN Consortium,   SLAP Consortium, Traynor Bryan , Singleton Adrew B. , Neto Miguel Mitne , Cauchi Ruben J. , Ophoff Roel A. , Wiedau-Pazos Martina , Lomen-Hoerth Catherine , van Deerlin Vivianna M. , Grosskreutz Julian , Rödiger 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 , Sachdev Perminder S. , Henders Anjali K. , Wallace Leanne , Carvalho Mamede de , Pinto Susana , Petri Susanne , Osmanovic Alma , Weber Markus , Rouleau Guy A. , Silani Vincenzo , Curtis Charles , Breen Gerome , Glass Jonathan , Brown Robert H. , Landers John E. , Shaw Christopher E. , Andersen Peter M. , Groen Ewout J.N. , Es Michael A. van , 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 , Damme Philip Van , van den Berg Leonard H. , Veldink Jan H. 
Published: March 2021

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions 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. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.