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van Rheenen, Wouter; McLaughlin, Russell L; van der Spek, Rick A A; Võsa, Urmo; Robinson, Matthew R; Yang, Jian; Fogh, Isabella; Koppers, Max; Blokhuis, Anna M; Harschnitz, Oliver; Schellevis, Raymond D; Menelaou, Androniki; Vajda, Alice; Lin, Kuang; Rogelj, Boris; Vrabec, Katarina; Ravnik-Glavač, Metka; Koritnik, Blaž; Zidar, Janez; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; Pinto, Susana; Mora, Jesus S; Rojas-García, Ricardo; Morrison, Karen E; Shaw, Pamela J; Sidle, Katie; Malaspina, Andrea; Topp, Simon; Petri, Susanne; Sendtner, Michael; Meyer, Thomas; Ophoff, Roel A; Staats, Kim A; Lomen-Hoerth, Catherine; Van Deerlin, Vivianna M; Trojanowski, John Q; Elman, Lauren; McCluskey, Leo; Basak, A Nazli; Tunca, Ceren; Meitinger, Thomas; Maurel, Cindy; Bensimon, Gilbert; Wood, Nicholas W; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Nöthen, Markus M; Amouyel, Philippe; Tzourio, Christophe; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; Blauw, Hylke M; de Visser, Marianne; Weber, Markus; Shaw, Christopher E; Smith, Bradley N; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P; Pensato, Viviana; Moglia, Cristina; Arcuti, Simona; Capozzo, Rosa; Filosto, Massimiliano; Muller, Bernard; Stuit, Robbert Jan; Fifita, Jennifer A; Nicholson, Garth A; Rowe, Dominic B; Kiernan, Matthew C; Witte, Otto W; Ringer, Thomas; Prell, Tino; Kurth, Ingo; Leigh, P Nigel; Casale, Federico; Chio, Adriano; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Ludolph, Albert C; Van Damme, Philip; Brown, Robert H; Landers, John E; Andersen, Peter M; Vourc'h, Patrick; Silani, Vincenzo; Wray, Naomi R; Visscher, Peter M; de Bakker, Paul I W; Pasterkamp, R Jeroen; Lewis, Cathryn M; Breen, Gerome; Al-Chalabi, Ammar; Veldink, Jan H
Nature genetics, 09/2016, Letnik: 48, Številka: 9Journal Article
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.
