Please use this identifier to cite or link to this item: https://www.um.edu.mt/library/oar/handle/123456789/103513
Title: Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Authors: Rheenen, Wouter van
Spek, Rick A.A. van der
Bakker, Mark K.
Vugt, Joke J.F.A. van
Hop, Paul J.
Zwamborn, Ramona A. J.
Klein, Niek de
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.
Eijk, Kristel R. van
Kooyman, Maarten
Byrne, Ross P.
Doherty, Mark
Heverin, Mark
Khleifat, Ahmad Al
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
Kooi, Anneke J. van der
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
Deerlin, Vivianna M. van
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
Carvalho, Mamede de
Pinto, Susana
Petri, Susanne
Weber, Markus
Rouleau, Guy A.
Silani, Vincenzo
Curtis, Charles J.
Breen, Gerome
Glass, Jonathan D.
Brown Jr., Robert H.
Landers, John E.
Shaw, Christopher E.
Andersen, Peter M.
Groen, Ewout J.N.
Es, Michael A. van
Jeroen Pasterkamp, R.
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
Damme, Philip Van
Berg, Leonard H. van den
Veldink, Jan H.
Authors: SLALOM Consortium
PARALS Consortium
SLAGEN Consortium
SLAP Consortium
Keywords: Genomes
Amyotrophic lateral sclerosis -- Diagnosis
Nervous system -- Degeneration
Issue Date: 2021
Publisher: Nature Publishing Group
Citation: Van Rheenen, W., Van Der Spek, R. A., Bakker, M. K., Van Vugt, J. J., Hop, P. J., Zwamborn, R. A., ... & Nicholson, G. A. (2021). Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nature genetics, 53(12), 1636-1648.
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.
URI: https://www.um.edu.mt/library/oar/handle/123456789/103513
Appears in Collections:Scholarly Works - FacM&SPB



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