| Literature DB >> 27455348 |
Wouter van Rheenen1, Aleksey Shatunov2, Annelot M Dekker1, Russell L McLaughlin3, Frank P Diekstra1, Sara L Pulit4, Rick A A van der Spek1, Urmo Võsa5, Simone de Jong6,7, Matthew R Robinson8, Jian Yang8, Isabella Fogh2,9, Perry Tc van Doormaal1, Gijs H P Tazelaar1, Max Koppers1,10, Anna M Blokhuis1,10, William Sproviero2, Ashley R Jones2, Kevin P Kenna11, Kristel R van Eijk1, Oliver Harschnitz1,10, Raymond D Schellevis1, William J Brands1, Jelena Medic1, Androniki Menelaou4, Alice Vajda12,13, Nicola Ticozzi9,14, Kuang Lin2, Boris Rogelj15,16, Katarina Vrabec17, Metka Ravnik-Glavač17,18, Blaž Koritnik19, Janez Zidar19, Lea Leonardis19, Leja Dolenc Grošelj19, Stéphanie Millecamps20, François Salachas20,21,22, Vincent Meininger23,24, Mamede de Carvalho25,26, Susana Pinto25,26, Jesus S Mora27, Ricardo Rojas-García28,29, Meraida Polak30,31, Siddharthan Chandran32,33, Shuna Colville32, Robert Swingler32, Karen E Morrison34, Pamela J Shaw35, John Hardy36, Richard W Orrell37, Alan Pittman36,38, Katie Sidle37, Pietro Fratta39, Andrea Malaspina40,41, Simon Topp2, Susanne Petri42, Susanne Abdulla43, Carsten Drepper44, Michael Sendtner44, Thomas Meyer45, Roel A Ophoff46,47,48, Kim A Staats48, Martina Wiedau-Pazos49, Catherine Lomen-Hoerth50, Vivianna M Van Deerlin51, John Q Trojanowski51, Lauren Elman52, Leo McCluskey52, A Nazli Basak53, Ceren Tunca53, Hamid Hamzeiy53, Yesim Parman54, Thomas Meitinger55, Peter Lichtner55, Milena Radivojkov-Blagojevic55, Christian R Andres56, Cindy Maurel56, Gilbert Bensimon57,58,59, Bernhard Landwehrmeyer60, Alexis Brice61,62,63,64,65, Christine A M Payan57,59, Safaa Saker-Delye66, Alexandra Dürr67, Nicholas W Wood68, Lukas Tittmann69, Wolfgang Lieb69, Andre Franke70, Marcella Rietschel71, Sven Cichon72,73,74,75,76, Markus M Nöthen72,73, Philippe Amouyel77, Christophe Tzourio78, Jean-François Dartigues78, Andre G Uitterlinden79,80, Fernando Rivadeneira79,80, Karol Estrada79, Albert Hofman80,81, Charles Curtis6,7, Hylke M Blauw1, Anneke J van der Kooi82, Marianne de Visser82, An Goris83, Markus Weber84, Christopher E Shaw2, Bradley N Smith2, Orietta Pansarasa85, Cristina Cereda85, Roberto Del Bo86, Giacomo P Comi86, Sandra D'Alfonso87, Cinzia Bertolin88, Gianni Sorarù88, Letizia Mazzini89, Viviana Pensato90, Cinzia Gellera90, Cinzia Tiloca9, Antonia Ratti9,14, Andrea Calvo91,92, Cristina Moglia91,92, Maura Brunetti91,92, Simona Arcuti93, Rosa Capozzo93, Chiara Zecca93, Christian Lunetta94, Silvana Penco95, Nilo Riva96, Alessandro Padovani97, Massimiliano Filosto97, Bernard Muller98, Robbert Jan Stuit98, Ian Blair99, Katharine Zhang99, Emily P McCann99, Jennifer A Fifita99, Garth A Nicholson99,100, Dominic B Rowe99, Roger Pamphlett101, Matthew C Kiernan102, Julian Grosskreutz103, Otto W Witte103, Thomas Ringer103, Tino Prell103, Beatrice Stubendorff103, Ingo Kurth104, Christian A Hübner104, P Nigel Leigh105, Federico Casale91, Adriano Chio91,92, Ettore Beghi106, Elisabetta Pupillo106, Rosanna Tortelli93, Giancarlo Logroscino107,108, John Powell2, Albert C Ludolph60, Jochen H Weishaupt60, Wim Robberecht83,109,110, Philip Van Damme83,109,110, Lude Franke5, Tune H Pers111,112,113,114,115, Robert H Brown11, Jonathan D Glass30,31, John E Landers11, Orla Hardiman12,13, Peter M Andersen60,116, Philippe Corcia56,117,118, Patrick Vourc'h56, Vincenzo Silani9,14, Naomi R Wray8, Peter M Visscher8,119, Paul I W de Bakker4,120, Michael A van Es1, R Jeroen Pasterkamp10, Cathryn M Lewis6,121, Gerome Breen6,7, Ammar Al-Chalabi2, Leonard H van den Berg1, Jan H Veldink1.
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.Entities:
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Year: 2016 PMID： 27455348 PMCID： PMC5556360 DOI： 10.1038/ng.3622
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 41.307