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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

2016; Nature Portfolio; Volume: 48; Issue: 9 Linguagem: Inglês

10.1038/ng.3622

1546-1718

Wouter van Rheenen, Aleksey Shatunov, Annelot M. Dekker, Russell L. McLaughlin, Frank P. Diekstra, Sara L. Pulit, Rick A. A. van der Spek, Urmo Võsa, Simone de Jong, Matthew R. Robinson, Jian Yang, Isabella Fogh, Perry Tc van Doormaal, Gijs Tazelaar, Max Koppers, Anna M. Blokhuis, William Sproviero, Ashley Jones, Kevin P. Kenna, Kristel R. van Eijk, Oliver Harschnitz, Raymond D. Schellevis, William J. Brands, Jelena Medic, Androniki Menelaou, Alice Vajda, Nicola Ticozzi, Kuang Lin, Boris Rogelj, Katarina Vrabec, Metka Ravnik‐Glavač, Blaž Koritnik, Janez Zidar, Lea Leonardis, Leja Dolenc Grošelj, Stéphanie Millecamps, François Salachas, Vincent Meininger, Mamede de Carvalho, Susana Pinto, Jesús S. Mora, Ricardo Rojas-García, Meraida Polak, Siddharthan Chandran, Shuna Colville, Robert Swingler, Karen Morrison, Pamela J. Shaw, John Hardy, Richard W. Orrell, Alan Pittman, Katie Sidle, Pietro Fratta, Andrea Malaspina, Simon Topp, Susanne Petri, Susanne Abdulla, Carsten Drepper, Michael Sendtner, Thomas Meyer, Roel A. Ophoff, Kim A. Staats, Martina Wiedau‐Pazos, Catherine Lomen‐Hoerth, Vivianna M. Van Deerlin, John Q. Trojanowski, Lauren Elman, Leo McCluskey, A. Nazlı Başak, Ceren Tunca, Hamid Hamzeiy, Yeşim Parman, Thomas Meitinger, Peter Lichtner, Milena Radivojkov‐Blagojevic, Christian Andrés, Cindy Maurel, Gilbert Bensimon, G. Bernhard Landwehrmeyer, Alexis Brice, Christine Payan, Safaa Saker-Delye, Alexandra Dürr, Nicholas Wood, Lukas Tittmann, Wolfgang Lieb, André Franke, Marcella Rietschel, Sven Cichon, Markus M. Nöthen, Philippe Amouyel, Christophe Tzourio, Jean‐François Dartigues, André G. Uitterlinden, Fernando Rivadeneira, Karol Estrada, Albert Hofman, Charles Curtis, Hylke M. Blauw, Anneke J. van der Kooi, Marianne de Visser, An Goris, Markus Weber, Christopher E. Shaw, Bradley Smith, Orietta Pansarasa, Cristina Cereda, Roberto Del Bo, Giacomo P. Comi, Sandra D’Alfonso, Cinzia Bertolin, Gianni Sorarù, Letizia Mazzini, Viviana Pensato, Cinzia Gellera, Cinzia Tiloca, Antonia Ratti, Andrea Calvo, Cristina Moglia, Maura Brunetti, Simona Arcuti, Rosa Capozzo, Chiara Zecca, Christian Lunetta, Silvana Penco, Nilo Riva, Alessandro Padovani, Massimiliano Filosto, Bernard Müller, Robbert Jan Stuit, Ian P. Blair, Katharine Zhang, Emily P. McCann, Jennifer A. Fifita, Garth A. Nicholson, Dominic B. Rowe, Roger Pamphlett, Matthew C. Kiernan, Julian Großkreutz, Otto W. Witte, Thomas Ringer, Tino Prell, Beatrice Stubendorff, Ingo Kurth, Christian A. Hübner, P. Nigel Leigh, Federico Casale, Adriano Chiò, Ettore Beghi, Elisabetta Pupillo, Rosanna Tortelli, Giancarlo Logroscino, John Powell, Albert C. Ludolph, Jochen H. Weishaupt, Wim Robberecht, Philip Van Damme, Lude Franke, Tune H. Pers, Robert H. Brown, Jonathan D. Glass, John E. Landers, Orla Hardiman, Peter M. Andersen, Philippe Corcia, Patrick Vourc’h, Vincenzo Silani, Naomi R. Wray, Peter M. Visscher, Paul I. W. de Bakker, Michael A. van Es, R. Jeroen Pasterkamp, Cathryn M. Lewis, Gerome Breen, Ammar Al‐Chalabi, Leonard H. van den Berg, Jan H. Veldink,

Neurological diseases and metabolism

Ammar Al-Chalabi, Jan Veldink and colleagues perform a genome-wide association study for amyotrophic lateral sclerosis (ALS) in 15,156 cases and 26,242 controls. They identify three new genome-wide-significant variants and establish ALS as a complex trait with a polygenic architecture, but with a distinct and important role for low-frequency variants. To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.