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

van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M; McLaughlin, Russell L; Diekstra, Frank P; Pulit, Sara L; van der Spek, Rick AA; Võsa, Urmo; de Jong, Simone; Robinson, Matthew R; Yang, Jian; Fogh, Isabella; van Doormaal, Perry Tc; Tazelaar, Gijs HP; 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 AM; 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 IW; van Es, Michael A; Pasterkamp, R Jeroen; Lewis, Cathryn M; Breen, Gerome; Al-Chalabi, Ammar; van den Berg, Leonard H; Veldink, Jan H

doi:10.1038/ng.3622

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

Author:

van Rheenen, Wouter

Shatunov, Aleksey ; Dekker, Annelot M ; McLaughlin, Russell L ; Diekstra, Frank P ; Pulit, Sara L ; van der Spek, Rick AA ; Võsa, Urmo ; de Jong, Simone ; Robinson, Matthew R ; Yang, Jian ; Fogh, Isabella ; van Doormaal, Perry Tc ; Tazelaar, Gijs HP ; 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 AM ; 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 IW ; van Es, Michael A ; Pasterkamp, R Jeroen ; Lewis, Cathryn M ; Breen, Gerome ; Al-Chalabi, Ammar ; van den Berg, Leonard H ; Veldink, Jan H

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, HEXANUCLEOTIDE REPEAT, ALS, SUSCEPTIBILITY, EFFICIENT, PITFALLS, COMPLEX, PROTEIN, C9ORF72, REGION, CILIA, Amyotrophic Lateral Sclerosis, Case-Control Studies, Cohort Studies, Cytoskeletal Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Munc18 Proteins, Mutation, Myelin Proteins, Netherlands, Proteins, PARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3001 Agricultural biotechnology, 3102 Bioinformatics and computational biology, 3105 Genetics

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.