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

van Rheenen, W. and Shatunov, A. and Dekker, A. M. and McLaughlin, R. L. and Diekstra, F. P. and Pulit, S. L. and van der Spek, R. A. and Vosa, U. and de Jong, S. and Robinson, M. R. and Yang, J. and Fogh, I. and van Doormaal, P. T. and Tazelaar, G. H. and Koppers, M. and Blokhuis, A. M. and Sproviero, W. and Jones, A. R. and Kenna, K. P. and van Eijk, K. R. and Harschnitz, O. and Schellevis, R. D. and Brands, W. J. and Medic, J. and Menelaou, A. and Vajda, A. and Ticozzi, N. and Lin, K. and Rogelj, B. and Vrabec, K. and Ravnik-Glavac, M. and Koritnik, B. and Zidar, J. and Leonardis, L. and Groselj, L. D. and Millecamps, S. and Salachas, F. and Meininger, V. and de Carvalho, M. and Pinto, S. and Mora, J. S. and Rojas-Garcia, R. and Polak, M. and Chandran, S. and Colville, S. and Swingler, R. and Morrison, K. E. and Shaw, P. J. and Hardy, J. and Orrell, R. W. and Pittman, A. and Sidle, K. and Fratta, P. and Malaspina, A. and Topp, S. and Petri, S. and Abdulla, S. and Drepper, C. and Sendtner, M. and Meyer, T. and Ophoff, R. A. and Staats, K. A. and Wiedau-Pazos, M. and Lomen-Hoerth, C. and Van Deerlin, V. M. and Trojanowski, J. Q. and Elman, L. and McCluskey, L. and Basak, A. N. and Tunca, C. and Hamzeiy, H. and Parman, Y. and Meitinger, T. and Lichtner, P. and Radivojkov-Blagojevic, M. and Andres, C. R. and Maurel, C. and Bensimon, G. and Landwehrmeyer, B. and Brice, A. and Payan, C. A. and Saker-Delye, S. and Durr, A. and Wood, N. W. and Tittmann, L. and Lieb, W. and Franke, A. and Rietschel, M. and Cichon, S. and Nothen, M. M. and Amouyel, P. and Tzourio, C. and Dartigues, J. F. and Uitterlinden, A. G. and Rivadeneira, F. and Estrada, K. and Hofman, A. and Curtis, C. and Blauw, H. M. and van der Kooi, A. J. and de Visser, M. and Goris, A. and Weber, M. and Shaw, C. E. and Smith, B. N. and Pansarasa, O. and Cereda, C. and Del Bo, R. and Comi, G. P. and D'Alfonso, S. and Bertolin, C. and Soraru, G. and Mazzini, L. and Pensato, V. and Gellera, C. and Tiloca, C. and Ratti, A. and Calvo, A. and Moglia, C. and Brunetti, M. and Arcuti, S. and Capozzo, R. and Zecca, C. and Lunetta, C. and Penco, S. and Riva, N. and Padovani, A. and Filosto, M. and Muller, B. and Stuit, R. J. and Parals Registry, and Slalom Group, and Slap Registry, and Fals Sequencing Consortium, and Slagen Consortium, and Nnipps Study Group, and Blair, I. and Zhang, K. and McCann, E. P. and Fifita, J. A. and Nicholson, G. A. and Rowe, D. B. and Pamphlett, R. and Kiernan, M. C. and Grosskreutz, J. and Witte, O. W. and Ringer, T. and Prell, T. and Stubendorff, B. and Kurth, I. and Hubner, C. A. and Leigh, P. N. and Casale, F. and Chio, A. and Beghi, E. and Pupillo, E. and Tortelli, R. and Logroscino, G. and Powell, J. and Ludolph, A. C. and Weishaupt, J. H. and Robberecht, W. and Van Damme, P. and Franke, L. and Pers, T. H. and Brown, R. H. and Glass, J. D. and Landers, J. E. and Hardiman, O. and Andersen, P. M. and Corcia, P. and Vourc'h, P. and Silani, V. and Wray, N. R. and Visscher, P. M. and de Bakker, P. I. and van Es, M. A. and Pasterkamp, R. J. and Lewis, C. M. and Breen, G. and Al-Chalabi, A. and van den Berg, L. H. and Veldink, J. H.. (2016) Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nature Genetics, 48 (9). pp. 1043-1048.

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Official URL: https://edoc.unibas.ch/61589/

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Human Genetics (Cichon)
UniBasel Contributors:Cichon, Sven
Item Type:Article, refereed
Article Subtype:Research Article
e-ISSN:1546-1718
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Apr 2019 15:56
Deposited On:16 Apr 2019 15:56

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