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

Van Rheenen, W.; Shatunov, A.; Dekker, A. M.; Mclaughlin, R. L.; Diekstra, F. P.; Pulit, S. L.; Van Der Spek, R. A. A.; Vosa, 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. R.; Kenna, K. P.; Van Eijk, K. R.; Harschnitz, O.; Schellevis, R. D.; Brands, W. J.; Medic, J.; Menelaou, A.; Vajda, A.; Ticozzi, N.; Lin, K.; Rogelj, B.; Vrabec, K.; Ravnik-Glava, M.; Koritnik, B.; Zidar, J.; Leonardis, L.; Groselj, L. D.; Millecamps, S.; Salachas, F.; Meininger, V.; De Carvalho, M.; Pinto, S.; Mora, J. S.; Rojas-Garcia, R.; Polak, M.; Chandran, S.; Colville, S.; Swingler, R.; Morrison, K. E.; Shaw, P. J.; Hardy, J.; Orrell, R. W.; Pittman, A.; Sidle, K.; Fratta, P.; Malaspina, A.; Topp, S.; Petri, S.; Abdulla, S.; Drepper, C.; Sendtner, M.; Meyer, T.; Ophoff, R. A.; Staats, K. A.; Wiedau-Pazos, M.; Lomen-Hoerth, C.; Van Deerlin, V. M.; Trojanowski, J. Q.; Elman, L.; Mccluskey, L.; Basak, A. N.; Tunca, C.; Hamzeiy, H.; Parman, Y.; Meitinger, T.; Lichtner, P.; Radivojkov-Blagojevic, M.; Andres, C. R.; Maurel, C.; Bensimon, G.; Landwehrmeyer, B.; Brice, A.; Payan, C. A. M.; Saker-Delye, S.; Durr, A.; Wood, N. W.; Tittmann, L.; Lieb, W.; Franke, A.; Rietschel, M.; Cichon, S.; Nothen, M. M.; Amouyel, P.; Tzourio, C.; Dartigues, J. -F.; Uitterlinden, A. G.; Rivadeneira, F.; Estrada, K.; Hofman, A.; Curtis, C.; Blauw, H. M.; Van Der Kooi, A. J.; De Visser, M.; Goris, A.; Weber, M.; Shaw, C. E.; Smith, B. N.; Pansarasa, O.; Cereda, C.; Del Bo, R.; Comi, G. P.; D'Alfonso, S.; Bertolin, C.; Soraru, G.; Mazzini, L.; Pensato, V.; Gellera, C.; Tiloca, C.; Ratti, A.; Calvo, A.; Moglia, C.; Brunetti, M.; Arcuti, S.; Capozzo, R.; Zecca, C.; Lunetta, C.; Penco, S.; Riva, N.; Padovani, A.; Filosto, M.; Muller, B.; Stuit, R. J.; Blair, I.; Zhang, K.; Mccann, E. P.; Fifita, J. A.; Nicholson, G. A.; Rowe, D. B.; Pamphlett, R.; Kiernan, M. C.; Grosskreutz, J.; Witte, O. W.; Ringer, T.; Prell, T.; Stubendorff, B.; Kurth, I.; Hubner, C. A.; Nigel Leigh, P.; Casale, F.; Chio, A.; Beghi, E.; Pupillo, E.; Tortelli, R.; Logroscino, G.; Powell, J.; Ludolph, A. C.; Weishaupt, J. H.; Robberecht, W.; Van Damme, P.; Franke, L.; Pers, T. H.; Brown, R. H.; Glass, J. D.; Landers, J. E.; Hardiman, O.; Andersen, P. M.; Corcia, P.; Vourc'H, P.; Silani, V.; Wray, N. R.; Visscher, P. M.; De Bakker, P. I. W.; Van Es, M. A.; Jeroen Pasterkamp, R.; Lewis, C. M.; Breen, G.; Al-Chalabi, A.; Van Den Berg, L. H.; Veldink, J. H.

doi:10.1038/ng.3622

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.