Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Autoren
Wouter van Rheenen, van der Spek, Rick A A, Mark Bakker, van Vugt, Joke J F A, Paul Hop, Ramona Zwamborn, Niek Klein, Harm-Jan Westra, Olivier Bakker, Patrick Deelen, Gemma Shireby, Eilis Hannon, Matthieu Moisse, Denis Baird, Restuadi Restuadi, Egor Dolzhenko, Annelot Dekker, Klara Gawor, Henk-Jan Westeneng, Gijs Tazelaar, Kristel van Eijk, Maarten Kooyman, Ross Byrne, Mark Doherty, Mark Heverin, Ahmad Al Khleifat, Alfredo Iacoangeli, Aleksey Shatunov, Nicola Ticozzi, Johnathan Cooper-Knock, Bradley Smith, Marta Gromicho, Siddharthan Chandran, Suvankar Pal, Karen Morrison, Pamela Shaw, John Hardy, Richard Orrell, Michael Sendtner, Thomas Meyer, Nazli Başak, van der Kooi, Anneke J, Antonia Ratti, Isabella Fogh, Cinzia Gellera, Giuseppe Lauria, Stefania Corti, Cristina Cereda, Daisy Sproviero, Sandra D'Alfonso, Gianni Sorarù, Gabriele Siciliano, Massimiliano Filosto, Alessandro Padovani, Adriano Chiò, Andrea Calvo, Cristina Moglia, Maura Brunetti, Antonio Canosa, Maurizio Grassano, Ettore Beghi, Elisabetta Pupillo, Giancarlo Logroscino, Beatrice Nefussy, Alma Osmanovic, Angelica Nordin, Yossef Lerner, Michal Zabari, Marc Gotkine, Robert Baloh, Shaughn Bell, Patrick Vourc'h, Philippe Corcia, Philippe Couratier, Stéphanie Millecamps, Vincent Meininger, François Salachas, Jesus Mora Pardina, Abdelilah Assialioui, Ricardo Rojas-García, Patrick Dion, Jay Ross, Albert Ludolph, Jochen Weishaupt, David Brenner, Axel Freischmidt, Gilbert Bensimon, Alexis Brice, Alexandra Durr, Christine Payan, Safa Saker-Delye, Nicholas Wood, Simon Topp, Rosa Rademakers, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Stephan Ripke, Alice Braun, Julia Kraft, David Whiteman, Catherine Olsen, Andre Uitterlinden, Albert Hofman, Marcella Rietschel, Sven Cichon, Markus Nöthen, Philippe Amouyel, Bryan Traynor, Andrew Singleton, Miguel Mitne Neto, Ruben Cauchi, Roel Ophoff, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna van Deerlin, Julian Grosskreutz, Annekathrin Roediger, Nayana Gaur, Alexander Jörk, Tabea Barthel, Erik Theele, Benjamin Ilse, Beatrice Stubendorff, Otto Witte, Robert Steinbach, Christian Hübner, Caroline Graff, Lev Brylev, Vera Fominykh, Vera Demeshonok, Anastasia Ataulina, Boris Rogelj, Blaž Koritnik, Janez Zidar, Metka Ravnik-Glavač, Damjan Glavač, Zorica Stević, Vivian Drory, Monica Povedano, Ian Blair, Matthew Kiernan, Beben Benyamin, Robert Henderson, Sarah Furlong, Susan Mathers, Pamela McCombe, Merrilee Needham, Shyuan Ngo, Garth Nicholson, Roger Pamphlett, Dominic Rowe, Frederik Steyn, Kelly Williams, Karen Mather, Perminder Sachdev, Anjali Henders, Leanne Wallace, Mamede Carvalho, Susana Pinto, Susanne Petri, Markus Weber, Guy Rouleau, Vincenzo Silani, Charles Curtis, Gerome Breen, Jonathan Glass, Robert Brown, John Landers, Christopher Shaw, Peter Andersen, Ewout Groen, Michael van Es, R. Pasterkamp, Dongsheng Fan, Fleur Garton, Allan McRae, George Davey Smith, Tom Gaunt, Michael Eberle, Jonathan Mill, Russell McLaughlin, Orla Hardiman, Kevin Kenna, Naomi Wray, Ellen Tsai, Heiko Runz, Lude Franke, Ammar Al-Chalabi, Philip van Damme, van den Berg, Leonard H, Jan Veldink
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.