1. 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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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, Needham, Merrilee, Ceroni, Mauro, Simoncini, Costanza, Gagliardi, Stella, Corrado, Lucia, Garton, Fleur C., Mazzini, Letizia, Westeneng, Henk Jan, Ross, Jay P., Valluzzi, Francesco, Aguggia, Marco, Raggi, Flavia, Rini, Augusto, Traynor, Bryan J., Singleton, Andrew B., Ngo, Shyuan T., Corcia, Philippe, Olsen, Catherine M., 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, Monica, 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, Siciliano, Gabriele, Petri, Susanne, Breen, Gerome, Weber, Markus, Rouleau, Guy A., Rojas García, Ricardo, Silani, Vincenzo, Amouyel, Philippe, Ghiglione, Paolo, Davey Smith, George, 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., Chiveri, Luca, Hardiman, Orla, Torrieri, Maria Claudia, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Padovani, Alessandro, Chandran, Siddharthan, Al Chalabi, Ammar, Assialioui, Abdelilah, Labate, Carmelo, Damme, Philip van, Ticozzi, Nicola, Palumbo, Francesca, Inghilleri, Maurizio, Chiò, Adriano, Pal, Suvankar, Lunetta, Christian, Jörk, Alexander, Cichon, Sven, Kraft, Julia, Morrison, Karen E., Ruiz, Luigi, Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Dion, Patrick A., Calvo, Andrea, Kooyman, Maarten, Başak, Nazli, Gerardi, Francesca, Simone, Isabella L., Kooi, Anneke J. van der, Ratti, Antonia, Ferrandi, Delfina, Fogh, Isabella, Ludolph, Albert C., Moglia, Cristina, Brunetti, Maura, Diamanti, Luca, Barthel, Tabea, Blair, Ian P., Es, Michael A. van, Gallone, Salvatore, Canosa, Antonio, Guerra, Vito, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Ferrarese, Carlo, Nefussy, Beatrice, Theele, Erik, Rinaldi, Fabrizio, Weishaupt, Jochen H., Kiernan, Matthew C., Barberis, Marco, Osmanovic, Alma, Baloh, Robert H., Nordin, Angelica, Lerner, Yossef, Vito, Nicoletta di, Zabari, Michal, Zoccolella, Stefano, Heverin, Mark, 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, Bensimon, Gilbert, Ilse, Benjamin, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Gentile, Salvatore, Moisse, Matthieu, Topp, Simon, 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, Delodovici, Maria Luisa, Furlong, Sarah, Bono, Giorgio, Manera, Umberto, Vasta, Rosario, Bombaci, Alessandro, Meineri, Piero, Mauro, Alessandro, Hannon, Eilis, Casale, Federico, Leone, Maurizio, Shaw, Christopher E., Fuda, Giuseppe, Salamone, Paolina, Mathers, Susan, Baird, Denis, Launaro, Nicola, Marchi, Fabiola de, Veldink, Jan H., Gellera, Cinzia, Salachas, François, Witte, Otto W., Andersen, Peter M., Bertolotto, Antonio, Gionco, Maurizio, Leotta, Daniela, Odddenino, Enrico, Slalom Consortium, Tamma, Filippo, Dotta, Michele, Lauria, Giuseppe, Steinbach, Robert, Imperiale, Daniele, Geda, Claudio, Dolzhenko, Egor, Cavallo, Roberto, 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, Comi, Giancarlo, Mccombe, Pamela A., Tiloca, Cinzia, Parals Consortium, Gawor, Klara, Peverelli, Silvia, Taroni, Franco, Pensato, Viviana, Castellotti, Barbara, Graff, Caroline, Comi, Giacomo P., Cereda, Cristina, Bo, Roberto del, Boero, Giovanni, Slagen Consortium, Vourc’h, Patrick, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), van Rheenen, Wouter, van der Spek, Rick AA, Bakker, Mark K, van Vugt, Joke JFA, Benyamin, Beben, Veldink, Jan H, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, SLAP Consortium, van Rheenen, W, van der Spek, R, Bakker, M, van Vugt, J, Hop, P, Zwamborn, R, de Klein, N, Westra, H, Bakker, O, Deelen, P, Shireby, G, Hannon, E, Moisse, M, Baird, D, Restuadi, R, Dolzhenko, E, Dekker, A, Gawor, K, Westeneng, H, Tazelaar, G, van Eijk, K, Kooyman, M, Byrne, R, Doherty, M, Heverin, M, Al Khleifat, A, Iacoangeli, A, Shatunov, A, Ticozzi, N, Cooper-Knock, J, Smith, B, Gromicho, M, Chandran, S, Pal, S, Morrison, K, Shaw, P, Hardy, J, Orrell, R, Sendtner, M, Meyer, T, Basak, N, van der Kooi, A, Ratti, A, Fogh, I, Gellera, C, Lauria, G, Corti, S, Cereda, C, Sproviero, D, D'Alfonso, S, Soraru, G, Siciliano, G, Filosto, M, Padovani, A, Chio, 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, R, Bell, S, Vourc'H, P, Corcia, P, Couratier, P, Millecamps, S, Meininger, V, Salachas, F, Mora Pardina, J, Assialioui, A, Rojas-Garcia, R, Dion, P, Ross, J, Ludolph, A, Weishaupt, J, Brenner, D, Freischmidt, A, Bensimon, G, Brice, A, Durr, A, Payan, C, Saker-Delye, S, Wood, N, Topp, S, Rademakers, R, Tittmann, L, Lieb, W, Franke, A, Ripke, S, Braun, A, Kraft, J, Whiteman, D, Olsen, C, Uitterlinden, A, Hofman, A, Rietschel, M, Cichon, S, Nothen, M, Amouyel, P, Traynor, B, Singleton, A, Mitne Neto, M, Cauchi, R, Ophoff, R, Wiedau-Pazos, M, Lomen-Hoerth, C, van Deerlin, V, Grosskreutz, J, Roediger, A, Gaur, N, Jork, A, Barthel, T, Theele, E, Ilse, B, Stubendorff, B, Witte, O, Steinbach, R, Hubner, C, Graff, C, Brylev, L, Fominykh, V, Demeshonok, V, Ataulina, A, Rogelj, B, Koritnik, B, Zidar, J, Ravnik-Glavac, M, Glavac, D, Stevic, Z, Drory, V, Povedano, M, Blair, I, Kiernan, M, Benyamin, B, Henderson, R, Furlong, S, Mathers, S, Mccombe, P, Needham, M, Ngo, S, Nicholson, G, Pamphlett, R, Rowe, D, Steyn, F, Williams, K, Mather, K, Sachdev, P, Henders, A, Wallace, L, de Carvalho, M, Pinto, S, Petri, S, Weber, M, Rouleau, G, Silani, V, Curtis, C, Breen, G, Glass, J, Brown, R, Landers, J, Shaw, C, Andersen, P, Groen, E, van Es, M, Pasterkamp, R, Fan, D, Garton, F, Mcrae, A, Davey Smith, G, Gaunt, T, Eberle, M, Mill, J, Mclaughlin, R, Hardiman, O, Kenna, K, Wray, N, Tsai, E, Runz, H, Franke, L, Al-Chalabi, A, Van Damme, P, van den Berg, L, Veldink, J, Ferrarese, C, Neurology, ANS - Neuroinfection & -inflammation, APH - Methodology, APH - Quality of Care, EURO-NMD, Internal Medicine, Epidemiology, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), van Rheenen, W., Van der Spek, R.A.A., Bakker, M.K., van Vugt, J.J.F.A., Hop, P.J., Zwamborn, R.A.J., de Klein, N., Westra, H.J., Bakker, O.B., Deelen, P., Shireby, G., Hannon, E., Moisse, M., Baird, D., Restuadi, R., Dolzhenko, E., Dekker, A.M., Gawor, K., Westeneng, H.J., Tazelaar, G.H.P., van Eijk, K.R., Kooyman, M., Byrne, R.P., Doherty, M., Heverin, M., Al Khleifat, A., Iacoangeli, A., Shatunov, A., Ticozzi, N., Cooper-Knock, J., Smith, B.N., Gromicho, M., Chandran, S., Pal, S., Morrison, K.E., Shaw, P.J., Hardy, J., Orrell, R.W., Sendtner, M., Meyer, T., van der Kooi, A.J., 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, R.H., Bell, S., Vourc'h, P., Corcia, P., Couratier, P., Millecamps, S., Meininger, V., Salachas, F., Mora Pardina, J.S., Assialioui, A., Rojas-García, R., Dion, P.A., Ross, J.P., Ludolph, A.C., Weishaupt, J.H., Brenner, D., Freischmidt, A., Bensimon, G., Brice, A., Durr, A., Payan, C.A.M., Saker-Delye, S., Wood, N.W., Topp, S., Rademakers, R., Tittmann, L., Lieb, W., Franke, A., Ripke, S., Kraft, J.,Whiteman, David C., Olsen, Catherine M., Uitterlinden, A.G., Hofman, A., Rietschel, M., Cichon, S., Nothen, M.M., Amouyel, P., Comi, G., Riva, N., Lunetta, C., Gerardi, F., Cotelli, M.S., Rinaldi, F., Chiveri, L., Guaita, M.C., Perrone, P., Ceroni, M., Diamanti, L., Ferrarese, C., Tremolizzo, L., Delodovici, M.L., Bono, G., Manera, U., Vasta, R., Bombaci, A., Casale, F., Fuda, G., Salamone, P., Iazzolino, B., Peotta, L., Cugnasco, P., De Marco, G., Torrieri, M.C., Palumbo, F., Gallone, S., Barberis, M., Sbaiz, L., Gentile, S., Mauro, A., Mazzini, L., De Marchi, F., Corrado, L., Bertolotto, A., Gionco, M., Leotta, D., Odddenino, E., Imperiale, D., Cavallo, R., Pignatta, P., De Mattei, M., Geda, C., Papurello, D.M., 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, G.P., Del Bo, R., Gagliardi, S., Raggi, F., Simoncini, C., Lo Gerfo, A., Inghilleri, M., Ferlini, A., Simone, I.L., 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, B.J., Singleton, A.B., Neto, M.M., Cauchi, R.J., Ophoff, R.A., Wiedau-Pazos, M., Lomen-Hoerth, C., van Deerlin, V.M., Grosskreutz, J., Roediger, A., Gaur, N., Jork, A., Barthel, T., Theele, E., Ilse, B., Stubendorff, B., Witte, O.W., Steinbach, R., Hubner, C.A., Graff, C., Brylev, L., Fominykh, V., Demeshonok, V., Ataulina, A., Rogelj, B., Koritnik, B., Zidar, J., Ravnik-Glavac, M., Glavac, D., Stevic, Z., Drory, V., Povedano, M., Blair, I.P., Kiernan, M.C., Benyamin, B., Henderson, R.D., Furlong, S., Mathers, S., McCombe, P.A, Needham, M., Ngo, S.T., Nicholson, G.A., Pamphlett, R., Rowe, D.B., Steyn, F.J., Williams, K.L., Mather, K.A., Sachdev, P.S., Henders, A.K., Wallace, L., de Carvalho, M., Pinto, S., Petri, S., Weber, M., Rouleau, G.A., Silani, V., Curtis, C.J., Breen, G., Glass, J.D., Brown, R.H., Landers, J.E., Shaw, C.E., Andersen, P.M., Groen, E.J.N, van Es, M.A., Pasterkamp, R.J., Fan, D.S., Garton, F.C., McRae, A.F., Smith, G.D., Gaunt, T.R., Eberle, M.A., Mill, J., McLaughlin, R.L., Hardiman, O., Kenna, K.P., Wray, N.R., Tsai, E.L., Runz, H., Franke, L., Al-Chalabi, A., Van Damme, P., van den Berg, L.H., Veldink, J.H., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine
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Male ,Genetics and heredity ,amyotrophic lateral sclerosis ,Neurologi ,Glutamine ,Medizin ,Genome-wide association study ,Disease ,SUSCEPTIBILITY ,Genome-wide association studies ,DISEASE ,Genètica mèdica ,0302 clinical medicine ,neurodegenerative disease ,genome-wide association study ,ALS, gene ,autophagy ,Risk Factors ,amyotrophic lateral sclerosi ,RNA-Seq ,Amyotrophic lateral sclerosis ,disease-modifying therapies ,blood [Cholesterol] ,Genetics ,Genetics & Heredity ,Neurons ,0303 health sciences ,Medical genetics ,Neurodegenerative diseases ,Genome-wide association ,Mendelian randomization ,Frontotemporal dementia ,Hexanucleotide repeat ,Mutant SOD1 ,Metaanalysis ,ALS ,Susceptibility ,Identification ,Brain ,Amyotrophic Lateral Sclerosis ,Cholesterol ,Disease Progression ,Female ,Humans ,Mendelian Randomization Analysis ,Microsatellite Repeats ,Neurodegenerative Diseases ,Quantitative Trait Loci ,Genome-Wide Association Study ,Mutation ,MUTANT SOD1 ,genetics [Amyotrophic Lateral Sclerosis] ,medicine.anatomical_structure ,Neurology ,risk factor ,metabolism [Neurons] ,MENDELIAN RANDOMIZATION ,nerve cell ,Life Sciences & Biomedicine ,quantitative trait locu ,Biology ,03 medical and health sciences ,Amyotrophic lateral sclerosis -- Diagnosis ,blood ,ddc:570 ,medicine ,degenerative disease ,Motor neuron disease ,human ,Genomes ,GENOME-WIDE ASSOCIATION ,gene ,Gene ,metabolism [Glutamine] ,METAANALYSIS ,030304 developmental biology ,Mendelian randomization analysi ,Science & Technology ,HEXANUCLEOTIDE REPEAT ,meta analysi ,IDENTIFICATION ,metabolism [Amyotrophic Lateral Sclerosis] ,FRONTOTEMPORAL DEMENTIA ,medicine.disease ,metabolism [Brain] ,genetics [Neurodegenerative Diseases] ,Expression quantitative trait loci ,disease exacerbation ,Neuron ,gemone ,genetic ,Vesicle-mediated transport ,metabolism ,Nervous system -- Degeneration ,Esclerosi lateral amiotròfica ,030217 neurology & neurosurgery - 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., Dutch Research Council (NWO); VENI Scheme Grant; VIDI Grant; Prinses Beatrix Spierfonds; Neuromuscular Fellowship Grant; Medical Research Council (MRC); Clinical Infrastructure Award; Epidemiology Unit; Integrative Epidemiology Unit; Canadian Institutes of Health Research; IWT; National Institute on Aging; National Health and Medical Research Council (NHMRC); Enabling Grant; NHMRC/Australian Research Council Strategic Award; NHMRC; NHMRC Centre of Research Excellence Grant; National Health and Medical Research Council of Australia (NHMRC) Research Fellowship; United Kingdom, Medical Research Council; Economic and Social Research Council; European Union (EU); Horizon 2020; European Community's Health Seventh Framework Programme; EuroMOTOR; European Research Council (ERC); Research and Innovation Programme; EScORIAL; ALS Foundation Netherlands; Alzheimer’s Society PhD Studentship; ARSla Funding; Biogen; University of Bristol; Motor Neurone Disease Association (MNDA); NIHR Maudsley Biomedical Research Centre; Dutch Ministry of Education, Culture, and Science; Netherlands Organization for Scientific Research (NWO; BRAINSCAPES); Gravitation Program; ALS Liga België; National Lottery of Belgium; KU Leuven Opening the Future Fund; KU Leuven Funds, “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund”; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Liga België; “Live now” Charity Foundation; Moscow ALS palliative Care Service; Canadian Institutes of Health; Research Australia; Ice Bucket Challenge Grant; NIH Intramural Research Programs; FightMND Mid-Career Fellowship; NIHR Senior Investigator; Sheffield NIHR Biomedical Research Centre; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre; Maudsley NHS Foundation Trust; King’s College London; NIHR Senior Investigator Award; Netherlands Organization for Health Research and Development; Vici Scheme; Netherlands Organization for Health Research and Development STRENGTH Project; PPP Allowance
- Published
- 2021
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