Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Authors
Van Rheenen, Woutervan der Spek, Rick A A
Bakker, Mark K
van Vugt, Joke J F A
Hop, Paul J
Zwamborn, Ramona A J
de Klein, Niek
Westra, Harm-Jan
Bakker, Olivier B
Deelen, Patrick
Shireby, Gemma
Hannon, Eilis
Moisse, Matthieu
Baird, Denis
Restuadi, Restuadi
Dolzhenko, Egor
Dekker, Annelot M
Gawor, Klara
Westeneng, Henk-Jan
Tazelaar, Gijs H P
van Eijk, Kristel R
Kooyman, Maarten
Byrne, Ross P
Doherty, Mark
Heverin, Mark
Al Khleifat, Ahmad
Iacoangeli, Alfredo
Shatunov, Aleksey
Ticozzi, Nicola
Cooper-Knock, Johnathan
Smith, Bradley N
Gromicho, Marta
Chandran, Siddharthan
Pal, Suvankar
Morrison, Karen E
Shaw, Pamela J
Hardy, John
Orrell, Richard W
Sendtner, Michael
Meyer, Thomas
Başak, Nazli
van der Kooi, Anneke J
Ratti, Antonia
Fogh, Isabella
Gellera, Cinzia
Lauria, Giuseppe
Corti, Stefania
Cereda, Cristina
Sproviero, Daisy
D'Alfonso, Sandra
Sorarù, Gianni
Siciliano, Gabriele
Filosto, Massimiliano
Padovani, Alessandro
Chiò, Adriano
Calvo, Andrea
Moglia, Cristina
Brunetti, Maura
Canosa, Antonio
Grassano, Maurizio
Beghi, Ettore
Pupillo, Elisabetta
Logroscino, Giancarlo
Nefussy, Beatrice
Osmanovic, Alma
Nordin, Angelica
Lerner, Yossef
Zabari, Michal
Gotkine, Marc
Baloh, Robert H
Bell, Shaughn
Vourc'h, Patrick
Corcia, Philippe
Couratier, Philippe
Millecamps, Stéphanie
Meininger, Vincent
Salachas, François
Mora Pardina, Jesus S
Assialioui, Abdelilah
Rojas-García, Ricardo
Dion, Patrick A
Ross, Jay P
Ludolph, Albert C
Weishaupt, Jochen H
Brenner, David
Freischmidt, Axel
Bensimon, Gilbert
Brice, Alexis
Durr, Alexandra
Payan, Christine A M
Saker-Delye, Safa
Wood, Nicholas W
Topp, Simon
Rademakers, Rosa
Tittmann, Lukas
Lieb, Wolfgang
Franke, Andre
Ripke, Stephan
Braun, Alice
Kraft, Julia
Whiteman, David C
Olsen, Catherine M
Uitterlinden, Andre G
Hofman, Albert
Rietschel, Marcella
Cichon, Sven
Nöthen, Markus M
Amouyel, Philippe
Traynor, Bryan J
Singleton, Andrew B
Mitne Neto, Miguel
Cauchi, Ruben J
Ophoff, Roel A
Wiedau-Pazos, Martina
Lomen-Hoerth, Catherine
Van Deerlin, Vivianna M
Grosskreutz, Julian
Roediger, Annekathrin
Gaur, Nayana
Jörk, Alexander
Barthel, Tabea
Theele, Erik
Ilse, Benjamin
Stubendorff, Beatrice
Witte, Otto W
Steinbach, Robert
Hübner, Christian A
Graff, Caroline
Brylev, Lev
Fominykh, Vera
Demeshonok, Vera
Ataulina, Anastasia
Rogelj, Boris
Koritnik, Blaž
Zidar, Janez
Ravnik-Glavač, Metka
Glavač, Damjan
Stević, Zorica
Drory, Vivian
Povedano, Monica
Blair, Ian P
Kiernan, Matthew C
Benyamin, Beben
Henderson, Robert D
Furlong, Sarah
Mathers, Susan
McCombe, Pamela A
Needham, Merrilee
Ngo, Shyuan T
Nicholson, Garth A
Pamphlett, Roger
Rowe, Dominic B
Steyn, Frederik J
Williams, Kelly L
Mather, Karen A
Sachdev, Perminder S
Henders, Anjali K
Wallace, Leanne
de Carvalho, Mamede
Pinto, Susana
Petri, Susanne
Weber, Markus
Rouleau, Guy A
Silani, Vincenzo
Curtis, Charles J
Breen, Gerome
Glass, Jonathan D
Brown, Robert H
Landers, John E
Shaw, Christopher E
Andersen, Peter M
Groen, Ewout J N
van Es, Michael A
Pasterkamp, R Jeroen
Fan, Dongsheng
Garton, Fleur C
McRae, Allan F
Davey Smith, George
Gaunt, Tom R
Eberle, Michael A
Mill, Jonathan
McLaughlin, Russell L
Hardiman, Orla
Kenna, Kevin P
Wray, Naomi R
Tsai, Ellen
Runz, Heiko
Franke, Lude
Al-Chalabi, Ammar
Van Damme, Philip
van den Berg, Leonard H
Veldink, Jan H
UMass Chan Affiliations
NeurologyDocument Type
Journal ArticlePublication Date
2021-12-06
Metadata
Show full item recordAbstract
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.Source
van Rheenen W, van der Spek RAA, Bakker MK, van Vugt JJFA, Hop PJ, Zwamborn RAJ, de Klein N, Westra HJ, Bakker OB, Deelen P, Shireby G, Hannon E, Moisse M, Baird D, Restuadi R, Dolzhenko E, Dekker AM, Gawor K, Westeneng HJ, 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, 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; SLALOM Consortium; PARALS Consortium; SLAGEN Consortium; SLAP Consortium; 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 Jr, 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. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021 Dec;53(12):1636-1648. doi: 10.1038/s41588-021-00973-1. Epub 2021 Dec 6. Erratum in: Nat Genet. 2022 Mar;54(3):361. PMID: 34873335; PMCID: PMC8648564.DOI
10.1038/s41588-021-00973-1Permanent Link to this Item
http://hdl.handle.net/20.500.14038/51986PubMed ID
34873335Notes
The authors from the Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA, are Robert H. Brown Jr. & John E. Landers.Rights
Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adap- tation, 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 statu- tory 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/. © The Author(s) 2021, corrected publication 2022; Attribution 4.0 InternationalDistribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1038/s41588-021-00973-1
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Except where otherwise noted, this item's license is described as Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adap- tation, 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 statu- tory 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/. © The Author(s) 2021, corrected publication 2022; Attribution 4.0 International