Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

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Item Type:	Article
Authors/Creators:	van Rheenen, W van der Spek, RAA Bakker, MK van Vugt, JJFA Hop, PJ Zwamborn, RAJ de Klein, N Westra, H-J Bakker, OB Deelen, P Shireby, G Hannon, E Moisse, M Baird, D Restuadi, R Dolzhenko, E Dekker, AM Gawor, K Westeneng, H-J Tazelaar, GHP van Eijk, KR Kooyman, M Byrne, RP Doherty, M Heverin, M Al Khleifat, A Iacoangeli, A Shatunov, A Ticozzi, N Cooper-Knock, J https://orcid.org/0000-0002-0873-8689 Smith, BN Gromicho, M Chandran, S Pal, S Morrison, KE Shaw, PJ Hardy, J Orrell, RW Sendtner, M Meyer, T Başak, N van der Kooi, AJ Ratti, A Fogh, I Gellera, C Lauria, G Corti, S Cereda, C Sproviero, D D’Alfonso, S Sorarù, G Siciliano, G Filosto, M Padovani, A Chiò, A Calvo, A Moglia, C Brunetti, M Canosa, A Grassano, M Beghi, E Pupillo, E Logroscino, G Nefussy, B Osmanovic, A Nordin, A Lerner, Y Zabari, M Gotkine, M Baloh, RH Bell, S Vourc’h, P Corcia, P Couratier, P Millecamps, S Meininger, V Salachas, F Mora Pardina, JS Assialioui, A Rojas-García, R Dion, PA Ross, JP Ludolph, AC Weishaupt, JH Brenner, D Freischmidt, A Bensimon, G Brice, A Durr, A Payan, CAM Saker-Delye, S Wood, NW Topp, S Rademakers, R Tittmann, L Lieb, W Franke, A Ripke, S Braun, A Kraft, J Whiteman, DC Olsen, CM Uitterlinden, AG Hofman, A Rietschel, M Cichon, S Nöthen, MM Amouyel, P Comi, G Riva, N Lunetta, C Gerardi, F Cotelli, MS Rinaldi, F Chiveri, L Guaita, MC Perrone, P Ceroni, M Diamanti, L Ferrarese, C Tremolizzo, L Delodovici, ML Bono, G Canosa, A Manera, U Vasta, R Bombaci, A Casale, F Fuda, G Salamone, P Iazzolino, B Peotta, L Cugnasco, P De Marco, G Torrieri, MC Palumbo, F Gallone, S Barberis, M Sbaiz, L Gentile, S Mauro, A Mazzini, L De Marchi, F Corrado, L D’Alfonso, S Bertolotto, A Gionco, M Leotta, D Odddenino, E Imperiale, D Cavallo, R Pignatta, P De Mattei, M Geda, C Papurello, DM Gusmaroli, G Comi, C Labate, C Ruiz, L Ferrandi, D Rota, E Aguggia, M Di Vito, N Meineri, P Ghiglione, P Launaro, N Dotta, M Di Sapio, A Giardini, G Tiloca, C Peverelli, S Taroni, F Pensato, V Castellotti, B Comi, GP Del Bo, R Ceroni, M Gagliardi, S Corrado, L Mazzini, L Raggi, F Simoncini, C Lo Gerfo, A Inghilleri, M Ferlini, A Simone, IL Passarella, B Guerra, V Zoccolella, S Nozzoli, C Mundi, C Leone, M Zarrelli, M Tamma, F Valluzzi, F Calabrese, G Boero, G Rini, A Traynor, BJ Singleton, AB Mitne Neto, M Cauchi, RJ Ophoff, RA Wiedau-Pazos, M Lomen-Hoerth, C van Deerlin, VM Grosskreutz, J Roediger, A Gaur, N Jörk, A Barthel, T Theele, E Ilse, B Stubendorff, B Witte, OW Steinbach, R Hübner, CA Graff, C Brylev, L Fominykh, V Demeshonok, V Ataulina, A Rogelj, B Koritnik, B Zidar, J Ravnik-Glavač, M Glavač, D Stević, Z Drory, V Povedano, M Blair, IP Kiernan, MC Benyamin, B Henderson, RD Furlong, S Mathers, S McCombe, PA Needham, M Ngo, ST Nicholson, GA Pamphlett, R Rowe, DB Steyn, FJ Williams, KL Mather, KA Sachdev, PS Henders, AK Wallace, L de Carvalho, M Pinto, S Petri, S Weber, M Rouleau, GA Silani, V Curtis, CJ Breen, G Glass, JD Brown, RH Landers, JE Shaw, CE Andersen, PM Groen, EJN van Es, MA Pasterkamp, RJ Fan, D Garton, FC McRae, AF Davey Smith, G Gaunt, TR Eberle, MA Mill, J McLaughlin, RL Hardiman, O Kenna, KP Wray, NR Tsai, E Runz, H Franke, L Al-Chalabi, A Van Damme, P van den Berg, LH Veldink, JH
Copyright, Publisher and Additional Information:	© 2021 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: December 2021 Published (online): 6 December 2021 Accepted: 18 October 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	14 Dec 2021 08:30
Last Modified:	21 Mar 2022 12:06
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s41588-021-00973-1
Related URLs:	Erratum/Corrigendum
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:181556

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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

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