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s41588-021-00973-1.pdf (8.87 MB)

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2021-12-01

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cc by (c) Rheenen, Wouter van et al, 2021
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/182764

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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https://doi.org/10.1038/s41588-021-00973-1

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A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. 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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Esclerosi lateral amiotròfica, Genètica mèdica

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Amyotrophic lateral sclerosis, Medical genetics

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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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, SICILIANO, Gabriele, PETRI, Susanne, BREEN, Gerome, WEBER, Markus, ROULEAU, Guy a., ROJAS GARCÍA, Ricardo, SILANI, Vincenzo, AMOUYEL, Philippe, GHIGLIONE, Paolo, DAVEY SMITH, George, NEEDHAM, Merrilee, CURTIS, Charles j., SHATUNOV, Aleksey, MILL, Jonathan, MCLAUGHLIN, Russell l., FILOSTO, Massimiliano, COMI, Cristoforo, GERFO, Annalisa lo, FERLINI, Alessandra, RIVA, Nilo, MORA PARDINA, Jesus s., CERONI, Mauro, CHIVERI, Luca, HARDIMAN, Orla, TORRIERI, Maria claudia, KENNA, Kevin p., WRAY, Naomi r., TSAI, Ellen, RUNZ, Heiko, FRANKE, Lude, PADOVANI, Alessandro, CHANDRAN, Siddharthan, SIMONCINI, Costanza, AL CHALABI, Ammar, ASSIALIOUI, Abdelilah, LABATE, Carmelo, DAMME, Philip van, TICOZZI, Nicola, PALUMBO, Francesca, INGHILLERI, Maurizio, CHIÒ, Adriano, PAL, Suvankar, LUNETTA, Christian, GAGLIARDI, Stella, JÖRK, Alexander, CICHON, Sven, KRAFT, Julia, MORRISON, Karen e., RUIZ, Luigi, SHAW, Pamela j., HARDY, John, ORRELL, Richard w., SENDTNER, Michael, MEYER, Thomas, CORRADO, Lucia, DION, Patrick a., CALVO, Andrea, KOOYMAN, Maarten, CERONI, Mauro, BAŞAK, Nazli, GERARDI, Francesca, SIMONE, Isabella l., KOOI, Anneke j. van der, RATTI, Antonia, FERRANDI, Delfina, GARTON, Fleur c., FOGH, Isabella, LUDOLPH, Albert c., MOGLIA, Cristina, BRUNETTI, Maura, DIAMANTI, Luca, BARTHEL, Tabea, BLAIR, Ian p., ES, Michael a. van, GALLONE, Salvatore, CANOSA, Antonio, MAZZINI, Letizia, GUERRA, Vito, GRASSANO, Maurizio, BEGHI, Ettore, PUPILLO, Elisabetta, LOGROSCINO, Giancarlo, FERRARESE, Carlo, NEFUSSY, Beatrice, THEELE, Erik, RINALDI, Fabrizio, WEISHAUPT, Jochen h., WESTENENG, Henk jan, KIERNAN, Matthew c., BARBERIS, Marco, OSMANOVIC, Alma, BALOH, Robert h., NORDIN, Angelica, LERNER, Yossef, VITO, Nicoletta di, ZABARI, Michal, ZOCCOLELLA, Stefano, HEVERIN, Mark, ROSS, Jay p., GOTKINE, Marc, GUAITA, Maria cristina, BRENNER, David, FREISCHMIDT, Axel, SBAIZ, Luca, BENYAMIN, Beben, GLASS, Jonathan d., LANDERS, John e., TAZELAAR, Gijs h. p., ROTA, Eugenia, VALLUZZI, Francesco, BENSIMON, Gilbert, ILSE, Benjamin, BRICE, Alexis, DURR, Alexandra, PAYAN, Christine a. m., SAKER-DELYE, Safa, WOOD, Nicholas w., GENTILE, Salvatore, MOISSE, Matthieu, TOPP, Simon, AGUGGIA, Marco, HENDERSON, Robert d., RADEMAKERS, Rosa, PERRONE, Patrizia, STUBENDORFF, Beatrice, BROWN, Robert h., RESTUADI, Restuadi, TREMOLIZZO, Lucio, MUNDI, Ciro, BERG, Leonard h. van den, PASSARELLA, Bruno, RAGGI, Flavia, DELODOVICI, Maria luisa, FURLONG, Sarah, BONO, Giorgio, CANOSA, Antonio, MANERA, Umberto, VASTA, Rosario, BOMBACI, Alessandro, MEINERI, Piero, MAURO, Alessandro, HANNON, Eilis, RINI, Augusto, CASALE, Federico, LEONE, Maurizio, SHAW, Christopher e., FUDA, Giuseppe, SALAMONE, Paolina, MATHERS, Susan, BAIRD, Denis, LAUNARO, Nicola, MAZZINI, Letizia, MARCHI, Fabiola de, TRAYNOR, Bryan j., VELDINK, Jan h., GELLERA, Cinzia, SALACHAS, François, WITTE, Otto w., CORRADO, Lucia, ANDERSEN, Peter m., D’ALFONSO, Sandra, BERTOLOTTO, Antonio, GIONCO, Maurizio, LEOTTA, Daniela, SINGLETON, Andrew b., ODDDENINO, Enrico, Slalom Consortium, TAMMA, Filippo, DOTTA, Michele, LAURIA, Giuseppe, STEINBACH, Robert, IMPERIALE, Daniele, GEDA, Claudio, DOLZHENKO, Egor, CAVALLO, Roberto, NGO, Shyuan t., PIGNATTA, Pietro, GROEN, Ewout j. n., COTELLI, Maria sofia, MATTEI, Marco de, CALABRESE, Gianluigi, SAPIO, Alessia di, GIARDINI, Guido, HÜBNER, Christian a., CORTI, Stefania, BELL, Shaughn, CORCIA, Philippe, COMI, Giancarlo, MCCOMBE, Pamela a., TILOCA, Cinzia, Parals Consortium, GAWOR, Klara, PEVERELLI, Silvia, TARONI, Franco, PENSATO, Viviana, CASTELLOTTI, Barbara, GRAFF, Caroline, OLSEN, Catherine m., COMI, Giacomo p., CEREDA, Cristina, BO, Roberto del, BOERO, Giovanni, Slagen Consortium, VOURC’H, Patrick, HOFMAN, Albert, VAN EIJK, Kristel r., PASTERKAMP, R. jeroen, TITTMANN, Lukas, IACOANGELI, Alfredo, MITNE NETO, Miguel, SPROVIERO, Daisy, CAUCHI, Ruben j., OPHOFF, Roel a., WIEDAU PAZOS, Martina, LOMEN-HOERTH, Catherine, DEERLIN, Vivianna m. van, NICHOLSON, Garth a., BRYLEV, Lev, WHITEMAN, David c., GROSSKREUTZ, Julian, FAN, Dongsheng, COURATIER, Philippe, ROEDIGER, Annekathrin, GAUR, Nayana, D’ALFONSO, Sandra, UITTERLINDEN, André g., PAMPHLETT, Roger, FOMINYKH, Vera, BYRNE, Ross p., LIEB, Wolfgang, IAZZOLINO, Barbara, DEKKER, Annelot m., Slap Consortium, DEMESHONOK, Vera, MILLECAMPS, Stéphanie, ATAULINA, Anastasia, ROGELJ, Boris, KORITNIK, Blaž, ZIDAR, Janez, RAVNIK-GLAVAČ, Metka, FRANKE, Andre, MCRAE, Allan f., ROWE, Dominic b., PEOTTA, Laura, COOPER-KNOCK, Johnathan, GLAVAČ, Damjan, DOHERTY, Mark, RIETSCHEL, Marcella, STEVIĆ, Zorica, DRORY, Vivian, MEININGER, Vincent, ZARRELLI, Michele, POVEDANO PANADES, Mónica, GAUNT, Tom r., STEYN, Frederik j., WILLIAMS, Kelly l., SMITH, Bradley n., CUGNASCO, Paolo, PAPURELLO, Diego maria, NOZZOLI, Cecilia, SORARÙ, Gianni, MATHER, Karen a., RIPKE, Stephan, NÖTHEN, Markus m., SACHDEV, Perminder s., HENDERS, Anjali k., WALLACE, Leanne, CARVALHO, Mamede de, GROMICHO, Marta, PINTO, Susana, MARCO, Giovanni de, AL KHLEIFAT, Ahmad, EBERLE, Michael a., BRAUN, Alice, GUSMAROLI, Graziano. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. _Nature Genetics_. 2021. Vol.  vol 53, núm. num 12, pàgs. 1636-1648. [consulta: 23 de gener de 2026]. ISSN: 1546-1718. [Disponible a: https://hdl.handle.net/2445/182764]

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