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

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.

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Item Type:	Article
Authors/Creators:	van Rheenen, W Shatunov, A Dekker, AM McLaughlin, RL Diekstra, FP Pulit, SL van der Spek, RA Võsa, U de Jong, S Robinson, MR Yang, J Fogh, I van Doormaal, PT Tazelaar, GH Koppers, M Blokhuis, AM Sproviero, W Jones, AR Kenna, KP van Eijk, KR Harschnitz, O Schellevis, RD Brands, WJ Medic, J Menelaou, A Vajda, A Ticozzi, N Lin, K Rogelj, B Vrabec, K Ravnik-Glavač, M Koritnik, B Zidar, J Leonardis, L Grošelj, LD Millecamps, S Salachas, F Meininger, V de Carvalho, M Pinto, S Mora, JS Rojas-García, R Polak, M Chandran, S Colville, S Swingler, R Morrison, KE Shaw, PJ https://orcid.org/0000-0002-8925-2567 Hardy, J Orrell, RW Pittman, A Sidle, K Fratta, P Malaspina, A Topp, S Petri, S Abdulla, S Drepper, C Sendtner, M Meyer, T Ophoff, RA Staats, KA Wiedau-Pazos, M Lomen-Hoerth, C Van Deerlin, VM Trojanowski, JQ Elman, L McCluskey, L Basak, AN Tunca, C Hamzeiy, H Parman, Y Meitinger, T Lichtner, P Radivojkov-Blagojevic, M Andres, CR Maurel, C Bensimon, G Landwehrmeyer, B Brice, A Payan, CA Saker-Delye, S Dürr, A Wood, NW Tittmann, L Lieb, W Franke, A Rietschel, M Cichon, S Nöthen, MM Amouyel, P Tzourio, C Dartigues, JF Uitterlinden, AG Rivadeneira, F Estrada, K Hofman, A Curtis, C Blauw, HM van der Kooi, AJ de Visser, M Goris, A Weber, M Shaw, CE Smith, BN Pansarasa, O Cereda, C Del Bo, R Comi, GP D'Alfonso, S Bertolin, C Sorarù, 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, RJ PARALS Registry SLALOM Group SLAP Registry FALS Sequencing Consortium SLAGEN Consortium NNIPPS Study Group Blair, I Zhang, K McCann, EP Fifita, JA Nicholson, GA Rowe, DB Pamphlett, R Kiernan, MC Grosskreutz, J Witte, OW Ringer, T Prell, T Stubendorff, B Kurth, I Hübner, CA Leigh, PN Casale, F Chio, A Beghi, E Pupillo, E Tortelli, R Logroscino, G Powell, J Ludolph, AC Weishaupt, JH Robberecht, W Van Damme, P Franke, L Pers, TH Brown, RH Glass, JD Landers, JE Hardiman, O Andersen, PM Corcia, P Vourc'h, P Silani, V Wray, NR Visscher, PM de Bakker, PI van Es, MA Pasterkamp, RJ Lewis, CM Breen, G Al-Chalabi, A van den Berg, LH Veldink, JH
Copyright, Publisher and Additional Information:	© 2016 Nature Publishing Group. This is an author produced version of a paper subsequently published in Nature Genetics. Uploaded in accordance with the publisher's self-archiving policy.
Dates:	Published: 25 July 2016 Published (online): 25 July 2016 Accepted: 20 June 2016
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	05 Oct 2016 08:19
Last Modified:	21 Apr 2017 10:39
Published Version:	http://dx.doi.org/10.1038/ng.3622
Status:	Published
Publisher:	Nature Publishing Group
Refereed:	Yes
Identification Number:	10.1038/ng.3622
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:105206

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

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