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, Rick A. A. van der Spek, Mark K. Bakker, Joke J.F.A. van Vugt, Paul J. Hop, Ramona A.J. Zwamborn, Niek de Klein, Harm-Jan Westra, Olivier B. Bakker, Patrick Deelen, Gemma Shireby, Eilís Hannon, Matthieu Moisse, Denis Baird, Restuadi Restuadi, Egor Dolzhenko, Annelot M. Dekker, Klara Gawor, Henk‐Jan Westeneng, Gijs H.P. Tazelaar, Kristel R. van Eijk, Maarten Kooyman, Ross P. Byrne, Mark A. 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 J. Shaw, John Hardy, Richard W. Orrell, Michael Sendtner, Thomas Meyer, Nazlı Başak, Anneke J. van der Kooi, Antonia Ratti, Isabella Fogh, Cinzia Gellera, Giuseppe Lauria, Stefania Corti, Cristina Cereda, Daisy Sproviero, Sandra D’Alfonso, Gianni Sorarú, 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 H. Baloh, Shaughn Bell, Patrick Vourc’h, Philippe Corcia, Philippe Couratier, Stéphanie Millecamps, Vincent Meininger, François Salachas, Jesús S. Mora Pardina, Abdelilah Assialioui, Ricardo Rojas-García, Patrick A. Dion, Jay P. Ross, Albert C. Ludolph, Jochen H. Weishaupt, Dávid Brenner, Axel Freischmidt, Gilbert Bensimon, Alexis Brice, Alexandra Durr, C. Payán, Safa Saker-Delye, Nicholas Wood, Simon Topp, Rosa Rademakers, Lukas Tittmann, Wolfgang Lieb, André Franke, Stephan Ripke, Alice Braun, Julia Kraft
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.