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

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 T C van Doormaal, Gijs H P Tazelaar, Max Koppers, Anna M. Blokhuis, William Sproviero, Ashley Jones, Kevin P. Kenna, Kristel R. van EijkOliver Harschnitz, Raymond D. Schellevis, William J. Brands, Jelena Medic, Androniki Menelaou, Alice Vajda, Nicola Ticozzi, Kuang Lin, Boris Rogelj, Katarina Vrabec, M. Ravnik-Glavac, Blaž Koritnik, J. Zidar, Lea Leonardis, Leja Dolenc Grošelj, Stéphanie Millecamps, François Salachas, Vincent Meininger, Mamede de Carvalho, Susana Pinto, Jesus S. Mora, Ricard Rojas-García, Meraida Polak, Siddharthan Chandran, Shuna Colville, Robert Swingler, Karen E. Morrison, Pamela J. Shaw, John Hardy, R. W. Orrell, Alan Pittman, K. C L Sidle, Pietro Fratta, A. 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. Nazli Basak, Ceren Tunca, Hamid Hamzeiy, Yesim Parman, Thomas Meitinger, Peter Lichtner, Milena Radivojkov-Blagojevic, Christian R. Andres, Cindy Maurel, G. Bensimon, Bernhard Landwehrmeyer, Alexis Brice, Christine A M Payan, Safaa Saker-Delye, Alexandra Dürr, Nicholas W. Wood, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Marcella Rietschel, Sven Cichon, Markus M. Nöthen, Philippe Amouyel, Christopher Tzourio, Jean François Dartigues, Andre G. Uitterlinden, Fernando Rivadeneira, Karol Estrada, Albert Hofman, Charles Curtis, Hylke M. Blauw, Anneke J. Van Der Kooi, M. De Visser, An Goris, Markus Weber, Christopher E. Shaw, Bradley N. Smith, Orietta Maria Ernestina Pansarasa, Cristina Cereda, Roberto Del Bo, Giacomo Pietro Comi, Sandra D'Alfonso, Cinzia Bertolin, Gianni Sorarù, Letizia Mazzini, Viviana Pensato, Cinzia Gellera, Cinzia Tiloca, Antonia Ratti, Andrea Calvo, C. Moglia, Maura Brunetti, Simona Arcuti, Rosa Capozzo, Chiara Zecca, Christian Lunetta, S. Penco, Nilo Riva, A. Padovani, Massimiliano Filosto, Bernard Muller, 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, T. Prell, Beatrice Stubendorff, Ingo Kurth, Christian A. Hübner, P. Nigel Leigh, Federico Casale, Adriano Chiò, E. Beghi, Elisabetta Pupillo, Rosanna Tortelli, Giancarlo Logroscino, John Powell, Albert C. Ludolph, Ettore Beghi, Elisabetta Pupillo, Philip van Damme, L. Franke, Tune H. Pers, Robert H. Brown, Jonathan D. Glass, John Landers, Orla Hardiman, Peter M. Andersen, Philippe Corcia, Patrick Vourc'h, Vincenzo Silani, Naomi R. Wray, Peter M. Visscher, P. I W De Bakker, Michael A. van Es, R. Jeroen Pasterkamp, Vincenzo Silani, G. Breen, Ammar Al-Chalabi, Leonard H. Van Den Berg, Jan Veldink

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalNature Genetics
DOIs
Publication statusAccepted/In press - Jul 25 2016

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ASJC Scopus subject areas

  • Medicine(all)
  • Genetics

Cite this

Van Rheenen, W., Shatunov, A., Dekker, A. M., McLaughlin, R. L., Diekstra, F. P., Pulit, S. L., van der Spek, R. A. A., Võsa, U., de Jong, S., Robinson, M. R., Yang, J., Fogh, I., van Doormaal, P. T. C., Tazelaar, G. H. P., Koppers, M., Blokhuis, A. M., Sproviero, W., Jones, A., Kenna, K. P., ... Veldink, J. (Accepted/In press). Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nature Genetics. https://doi.org/10.1038/ng.3622