van Rheenen Wouter, Shatunov Aleksey, Dekker Annelot M, McLaughlin Russell L, Diekstra Frank P, Pulit Sara L, van der Spek Rick A A, Võsa Urmo, de Jong Simone, Robinson Matthew R, Yang Jian, Fogh Isabella, van Doormaal Perry Tc, Tazelaar Gijs H P, Koppers Max, Blokhuis Anna M, Sproviero William, Jones Ashley R, Kenna Kevin P, van Eijk Kristel R, Harschnitz Oliver, Schellevis Raymond D, Brands William J, Medic Jelena, Menelaou Androniki, Vajda Alice, Ticozzi Nicola, Lin Kuang, Rogelj Boris, Vrabec Katarina, Ravnik-Glavač Metka, Koritnik Blaž, Zidar Janez, Leonardis Lea, Grošelj Leja Dolenc, Millecamps Stéphanie, Salachas François, Meininger Vincent, de Carvalho Mamede, Pinto Susana, Mora Jesus S, Rojas-García Ricardo, Polak Meraida, Chandran Siddharthan, Colville Shuna, Swingler Robert, Morrison Karen E, Shaw Pamela J, Hardy John, Orrell Richard W, Pittman Alan, Sidle Katie, Fratta Pietro, Malaspina Andrea, Topp Simon, Petri Susanne, Abdulla Susanne, Drepper Carsten, Sendtner Michael, Meyer Thomas, Ophoff Roel A, Staats Kim A, Wiedau-Pazos Martina, Lomen-Hoerth Catherine, Van Deerlin Vivianna M, Trojanowski John Q, Elman Lauren, McCluskey Leo, Basak A Nazli, Tunca Ceren, Hamzeiy Hamid, Parman Yesim, Meitinger Thomas, Lichtner Peter, Radivojkov-Blagojevic Milena, Andres Christian R, Maurel Cindy, Bensimon Gilbert, Landwehrmeyer Bernhard, Brice Alexis, Payan Christine A M, Saker-Delye Safaa, Dürr Alexandra, Wood Nicholas W, Tittmann Lukas, Lieb Wolfgang, Franke Andre, Rietschel Marcella, Cichon Sven, Nöthen Markus M, Amouyel Philippe, Tzourio Christophe, Dartigues Jean-François, Uitterlinden Andre G, Rivadeneira Fernando, Estrada Karol, Hofman Albert, Curtis Charles, Blauw Hylke M, van der Kooi Anneke J, de Visser Marianne, Goris An, Weber Markus, Shaw Christopher E, Smith Bradley N, Pansarasa Orietta, Cereda Cristina, Del Bo Roberto, Comi Giacomo P, D'Alfonso Sandra, Bertolin Cinzia, Sorarù Gianni, Mazzini Letizia, Pensato Viviana, Gellera Cinzia, Tiloca Cinzia, Ratti Antonia, Calvo Andrea, Moglia Cristina, Brunetti Maura, Arcuti Simona, Capozzo Rosa, Zecca Chiara, Lunetta Christian, Penco Silvana, Riva Nilo, Padovani Alessandro, Filosto Massimiliano, Muller Bernard, Stuit Robbert Jan, Blair Ian, Zhang Katharine, McCann Emily P, Fifita Jennifer A, Nicholson Garth A, Rowe Dominic B, Pamphlett Roger, Kiernan Matthew C, Grosskreutz Julian, Witte Otto W, Ringer Thomas, Prell Tino, Stubendorff Beatrice, Kurth Ingo, Hübner Christian A, Leigh P Nigel, Casale Federico, Chio Adriano, Beghi Ettore, Pupillo Elisabetta, Tortelli Rosanna, Logroscino Giancarlo, Powell John, Ludolph Albert C, Weishaupt Jochen H, Robberecht Wim, Van Damme Philip, Franke Lude, Pers Tune H, Brown Robert H, Glass Jonathan D, Landers John E, Hardiman Orla, Andersen Peter M, Corcia Philippe, Vourc'h Patrick, Silani Vincenzo, Wray Naomi R, Visscher Peter M, de Bakker Paul I W, van Es Michael A, Pasterkamp R Jeroen, Lewis Cathryn M, Breen Gerome, Al-Chalabi Ammar, van den Berg Leonard H, Veldink Jan H
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London, UK.
Nat Genet. 2016 Sep;48(9):1043-8. doi: 10.1038/ng.3622. Epub 2016 Jul 25.
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.
为了阐明肌萎缩侧索硬化症（ALS）的遗传结构并找到相关基因座，我们从全基因组测序的ALS患者及匹配的对照（n = 1,861）中组装了一个定制的归因参考面板。通过对12,577例病例和23,475例对照进行归因和混合模型关联分析，并结合一个独立重复队列中的2,579例病例和2,767例对照，我们在21号染色体上精细定位了一个新的风险基因座，并确定C21orf2为与ALS风险相关的基因。此外，我们将MOBP和SCFD1鉴定为新的相关风险基因座。我们证实了ALS是一种具有多基因结构的复杂遗传性状。此外，我们估计基于单核苷酸多态性（SNP）的遗传率为8.5%，低频变异（频率为1-10%）具有独特且重要的作用。这项研究促使人们对具有全基因组覆盖的更大样本进行研究，以识别构成ALS风险基础的罕见因果变异。
