208 results on '"Sproviero, William"'
Search Results
2. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.
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van Rheenen, Wouter, Shatunov, Aleksey, Dekker, Annelot M, McLaughlin, Russell L, Diekstra, Frank P, Pulit, Sara L, van der Spek, Rick AA, Võsa, Urmo, de Jong, Simone, Robinson, Matthew R, Yang, Jian, Fogh, Isabella, van Doormaal, Perry Tc, Tazelaar, Gijs HP, Koppers, Max, Blokhuis, Anna M, Sproviero, William, Jones, Ashley R, Kenna, Kevin P, van Eijk, Kristel R, Harschnitz, Oliver, Schellevis, Raymond D, Brands, William J, Medic, Jelena, Menelaou, Androniki, Vajda, Alice, Ticozzi, Nicola, Lin, Kuang, Rogelj, Boris, Vrabec, Katarina, Ravnik-Glavač, Metka, Koritnik, Blaž, Zidar, Janez, Leonardis, Lea, Grošelj, Leja Dolenc, Millecamps, Stéphanie, Salachas, François, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S, Rojas-García, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E, Shaw, Pamela J, Hardy, John, Orrell, Richard W, Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Topp, Simon, Petri, Susanne, Abdulla, Susanne, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Ophoff, Roel A, Staats, Kim A, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M, Trojanowski, John Q, Elman, Lauren, McCluskey, Leo, Basak, A Nazli, Tunca, Ceren, Hamzeiy, Hamid, Parman, Yesim, Meitinger, Thomas, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Andres, Christian R, Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine AM, Saker-Delye, Safaa, Dürr, Alexandra, Wood, Nicholas W, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-François, Uitterlinden, Andre G, Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, and Blauw, Hylke M
- Subjects
PARALS Registry ,SLALOM Group ,SLAP Registry ,FALS Sequencing Consortium ,SLAGEN Consortium ,NNIPPS Study Group ,Humans ,Amyotrophic Lateral Sclerosis ,Genetic Predisposition to Disease ,Proteins ,Cytoskeletal Proteins ,Myelin Proteins ,Case-Control Studies ,Cohort Studies ,Mutation ,Netherlands ,Munc18 Proteins ,Genome-Wide Association Study ,Neurosciences ,Rare Diseases ,Brain Disorders ,Biotechnology ,Prevention ,Human Genome ,Neurodegenerative ,Genetics ,ALS ,Aetiology ,2.1 Biological and endogenous factors ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
- Published
- 2016
3. Describing the effects of iron dyshomeostasis on cognitive function and dementia in UK Biobank
- Author
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Winchester, Laura M, primary, Newby, Danielle, additional, Sproviero, William, additional, Gallacher, John, additional, Bauermeister, Sarah, additional, and Nevado‐Holgado, Alejo J, additional
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- 2023
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4. Opioid use, postoperative complications, and implant survival after unicompartmental versus total knee replacement: a population-based network study
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Burn, Edward, Weaver, James, Morales, Daniel, Prats-Uribe, Albert, Delmestri, Antonella, Strauss, Victoria Y, He, Ying, Robinson, Danielle E, Pinedo-Villanueva, Rafael, Kolovos, Spyros, Duarte-Salles, Talita, Sproviero, William, Yu, Dahai, Van Speybroeck, Michel, Williams, Ross, John, Luis H, Hughes, Nigel, Sena, Anthony G, Costello, Ruth, Birlie, Belay, Culliford, David, O'Leary, Caroline, Morgan, Henry, Burkard, Theresa, Prieto-Alhambra, Daniel, and Ryan, Patrick
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- 2019
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5. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
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Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, Georgios, Appel, Stanley H., Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard, Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Allen, Andrew S., Appel, Stanley, Bedlack, Richard S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Ticozzi, Nicola, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, D’Alfonso, Sandra, Corrado, Lucia, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Mazzini, Letizia, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Al Kheifat, Ahmad, Al-Chalabi, Ammar, Andersen, Peter, Basak, A. Nazli, Blair, Ian P., Chio, Adriano, Cooper-Knock, Jonathan, de Carvalho, Mamede, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hardiman, Orla, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Kooyman, Maarten, Landers, John, McLaughlin, Russell, Middelkoop, Bas, Mill, Jonathan, Neto, Miguel Mitne, Moisse, Mattieu, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shatunov, Aleksey, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van der Spek, Rick, van Eijk, Kristel, van Es, Michael, van Rheenen, Wouter, van Vugt, Joke, Veldink, Jan, Weber, Markus, Williams, Kelly L., Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., Murphy, Natalie A., van Vugt, Joke J.F.A., Geiger, Joshua T., Van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Messina, Sonia, Simone, Isabella L., Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Wyman, Stacia K., LeNail, Alex, Van Eyk, Jennifer E., Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L.M.A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J.L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Van Eijk, Kristel R., Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Fifita, Jennifer A., Nicholson, Garth A., Esteban-Pérez, Jesús, García-Redondo, Alberto, Rogaeva, Ekaterina, Zinman, Lorne, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Van Damme, Philip, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.
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- 2018
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6. Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder vs Control Individuals
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Amin, Najaf, primary, Liu, Jun, additional, Bonnechere, Bruno, additional, MahmoudianDehkordi, Siamak, additional, Arnold, Matthias, additional, Batra, Richa, additional, Chiou, Yu-Jie, additional, Fernandes, Marco, additional, Ikram, M. Arfan, additional, Kraaij, Robert, additional, Krumsiek, Jan, additional, Newby, Danielle, additional, Nho, Kwangsik, additional, Radjabzadeh, Djawad, additional, Saykin, Andrew J., additional, Shi, Liu, additional, Sproviero, William, additional, Winchester, Laura, additional, Yang, Yang, additional, Nevado-Holgado, Alejo J., additional, Kastenmüller, Gabi, additional, Kaddurah-Daouk, Rima, additional, and van Duijn, Cornelia M., additional
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- 2023
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7. Integrating the environmental and genetic architectures of mortality and aging
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Argentieri, M. Austin, primary, Amin, Najaf, additional, Nevado-Holgado, Alejo J., additional, Sproviero, William, additional, Collister, Jennifer A., additional, Keestra, Sarai M., additional, Doherty, Aiden, additional, Hunter, David J., additional, Alvergne, Alexandra, additional, and van Duijn, Cornelia M., additional
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- 2023
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8. The impact of Short Tandem Repeats on grey matter brain imaging derived phenotypes in UK Biobank
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Sproviero, William, primary, Ghose, Upamanyu, additional, Winchester, Laura M, additional, Fernandes, Marco, additional, Newby, Danielle, additional, Sproviero, Daisy, additional, Amin, Najaf, additional, Smets, Bart, additional, He, Karen Y., additional, Khramtsova, Ekaterina A., additional, Patel, Parth, additional, Sarver, Brice A. J., additional, Howe, Trevor, additional, Black, Mary Helen, additional, van Duijn, Cornelia, additional, and Nevado-Holgado, Alejo, additional
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- 2023
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9. C9orf72 intermediate expansions of 24–30 repeats are associated with ALS
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Iacoangeli, Alfredo, Al Khleifat, Ahmad, Jones, Ashley R., Sproviero, William, Shatunov, Aleksey, Opie-Martin, Sarah, Alzheimer’s Disease Neuroimaging Initiative, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Fogh, Isabella, Dobson, Richard J., Newhouse, Stephen J., and Al-Chalabi, Ammar
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- 2019
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10. Interplay of the human exposome, metabolome and gut microbiome in dementia and major depression
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van Duijn, Cornelia M, primary, Amin, Najaf, additional, Liu, Jun, additional, Bonnechere, Bruno, additional, MahmoudianDehkordi, Siamak, additional, Arnold, Matthias, additional, Batra, Richa, additional, Chiou, Yu‐Jie, additional, Fernandes, Marco, additional, Ikram, M. Arfan, additional, Kraaij, Robert, additional, Krumsiek, Jan, additional, Newby, Danielle, additional, Nho, Kwangsik, additional, Radjabzadeh, Djawad, additional, Saykin, Andrew J., additional, Shi, Liu, additional, Sproviero, William, additional, Winchester, Laura M, additional, Yang, Yang, additional, Nevado‐Holgado, Alejo J, additional, Kastenmüller, Gabi, additional, and Kaddurah‐Daouk, Rima, additional
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- 2022
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11. Comparative effect of metformin versus sulfonylureas with dementia and Parkinson’s disease risk in US patients over 50 with type 2 diabetes mellitus
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Newby, Danielle, primary, Linden, Andrew Brent, additional, Fernandes, Marco, additional, Molero, Yasmina, additional, Winchester, Laura, additional, Sproviero, William, additional, Ghose, Upamanyu, additional, Li, Qingqin S, additional, Launer, Lenore J, additional, Duijn, Cornelia M van, additional, and Nevado-Holgado, Alejo J, additional
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- 2022
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12. Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort
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Tazelaar, Gijs H.P., Dekker, Annelot M., van Vugt, Joke J.F.A., van der Spek, Rick A., Westeneng, Henk-Jan, Kool, Lindy J.B.G., Kenna, Kevin P., van Rheenen, Wouter, Pulit, Sara L., McLaughlin, Russell L., Sproviero, William, Iacoangeli, Alfredo, Hübers, Annemarie, Brenner, David, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Panadés, Monica Povedano, Mora Pardina, Jesus S., Glass, Jonathan D., Hardiman, Orla, Al-Chalabi, Ammar, van Damme, Philip, Robberecht, Wim, Landers, John E., Ludolph, Albert C., Weishaupt, Jochen H., van den Berg, Leonard H., Veldink, Jan H., and van Es, Michael A.
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- 2019
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13. The multistep hypothesis of ALS revisited: The role of genetic mutations
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Chiò, Adriano, Mazzini, Letizia, DʼAlfonso, Sandra, Corrado, Lucia, Canosa, Antonio, Moglia, Cristina, Manera, Umberto, Bersano, Enrica, Brunetti, Maura, Barberis, Marco, Veldink, Jan H., van den Berg, Leonard H., Pearce, Neil, Sproviero, William, McLaughlin, Russell, Vajda, Alice, Hardiman, Orla, Rooney, James, Mora, Gabriele, Calvo, Andrea, and Al-Chalabi, Ammar
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- 2018
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14. Interplay of Human Metabolome and Gut Microbiome in Major Depression
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Amin, Najaf, primary, Liu, Jun, additional, Bonnechere, Bruno, additional, MehmoudianDehkordi, Siamak, additional, Arnold, Matthias, additional, Batra, Richa, additional, Chiou, Yu-Jie, additional, Fernandes, Marco, additional, Ikram, M. Arfan, additional, Kraaij, Robert, additional, Krumsiek, Jan, additional, Newby, Danielle, additional, Nho, Kwangsik, additional, Radjabzadeh, Djawad, additional, Saykin, Andrew J, additional, Shi, Liu, additional, Sproviero, William, additional, Winchester, Laura, additional, Yang, Yang, additional, Nevado-Holgado, Alejo J, additional, Kastenmüller, Gabi, additional, Kaddurah-Daouk, Rima F, additional, and van Duijn, Cornelia M, additional
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- 2022
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15. Genome wide association neural networks (GWANN) identify novel genes linked to family history of Alzheimer’s disease in the UK Biobank
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Ghose, Upamanyu, primary, Sproviero, William, additional, Winchester, Laura, additional, Fernandes, Marco, additional, Newby, Danielle, additional, Ulm, Brittany S., additional, Shi, Liu, additional, Liu, Qiang, additional, Adams, Cassandra, additional, Albukhari, Ashwag, additional, Almansouri, Majid, additional, Choudhry, Hani, additional, van Duijn, Cornelia, additional, and Nevado-Holgado, Alejo, additional
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- 2022
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16. Interplay of the human exposome, metabolome and gut microbiome in dementia and major depression
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van Duijn, Cornelia M., Amin, Najaf, Liu, Jun, Bonnechere, Bruno, MahmoudianDehkordi, Siamak, Arnold, Matthias, Batra, Richa, Chiou, Yu Jie, Fernandes, Marco, Ikram, M. Arfan, Kraaij, Robert, Krumsiek, Jan, Newby, Danielle, Nho, Kwangsik, Radjabzadeh, Djawad, Saykin, Andrew J., Shi, Liu, Sproviero, William, Winchester, Laura M., Yang, Yang, Nevado-Holgado, Alejo J., Kastenmüller, Gabi, Kaddurah-Daouk, Rima, van Duijn, Cornelia M., Amin, Najaf, Liu, Jun, Bonnechere, Bruno, MahmoudianDehkordi, Siamak, Arnold, Matthias, Batra, Richa, Chiou, Yu Jie, Fernandes, Marco, Ikram, M. Arfan, Kraaij, Robert, Krumsiek, Jan, Newby, Danielle, Nho, Kwangsik, Radjabzadeh, Djawad, Saykin, Andrew J., Shi, Liu, Sproviero, William, Winchester, Laura M., Yang, Yang, Nevado-Holgado, Alejo J., Kastenmüller, Gabi, and Kaddurah-Daouk, Rima
- Abstract
Background: The pathogenesis of dementia and depression is complex involving the interplay of genetic and environmental risk factors including diet, life-style and the gut microbiome. Dementia and depression co-occur and metabolomics studies may shed light on the interplay of the various risk factors. Methods: We have studied the metabolome of 118,466 individuals including 8462 cases with a history of major depression (MDD) and 1,364 patients who developed dementia during follow-up from the UK Biobank (UKB). The human metabolome was profiled using the Nightingale platform. Result: For both disorders, we find direct evidence that metabolites involved in the tricarboxylic acid (TCA) cycle are altered in patients, albeit that different metabolites emerge as the most significant drivers in the two disorders. Both dementia and MDD dementia patients show a marked change in the HDL/VLDL axis in blood, with similar changes in particular small and extra large HDL subfractions seen in patients with MDD and those who develop depression in the future. The two patients groups further show similar changes in fat metabolism as measured by omega 3, omega 6 and PUFA levels. When comparing metabolic profiles over environmental risk factors for MDD and dementia, we find that MDD clusters with dementia risk factors physical activity, history of previous smoking and social isolation. Integrating the metabolic profiles of major depression and the gut microbiome we find that the gut microbiome may be a key mediator in the relationship between various metabolites involved in the HDL subfractions associated to both MDD and dementia. Conclusion: Our study shows that energy and fat metabolism is disturbed in patients with MDD as well as patients who develop dementia in the future and that the interplay between the genome, exposome, gut microbiome, human metabolome may play role in the co-occurrence of major depression and dementia.
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- 2022
17. Comparative effect of metformin versus sulfonylureas with dementia and Parkinson's disease risk in US patients over 50 with type 2 diabetes mellitus
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Newby, Danielle, Linden, Andrew Brent, Fernandes, Marco, Molero, Yasmina, Winchester, Laura, Sproviero, William, Ghose, Upamanyu, Li, Qingqin S., Launer, Lenore J., Duijn, Cornelia M.van, Nevado-Holgado, Alejo J., Newby, Danielle, Linden, Andrew Brent, Fernandes, Marco, Molero, Yasmina, Winchester, Laura, Sproviero, William, Ghose, Upamanyu, Li, Qingqin S., Launer, Lenore J., Duijn, Cornelia M.van, and Nevado-Holgado, Alejo J.
- Abstract
INTRODUCTION: Type 2 diabetes is a risk factor for dementia and Parkinson's disease (PD). Drug treatments for diabetes, such as metformin, could be used as novel treatments for these neurological conditions. Using electronic health records from the USA (OPTUM EHR) we aimed to assess the association of metformin with all-cause dementia, dementia subtypes and PD compared with sulfonylureas. RESEARCH DESIGN AND METHODS: A new user comparator study design was conducted in patients ≥50 years old with diabetes who were new users of metformin or sulfonylureas between 2006 and 2018. Primary outcomes were all-cause dementia and PD. Secondary outcomes were Alzheimer's disease (AD), vascular dementia (VD) and mild cognitive impairment (MCI). Cox proportional hazards models with inverse probability of treatment weighting (IPTW) were used to estimate the HRs. Subanalyses included stratification by age, race, renal function, and glycemic control. RESULTS: We identified 96 140 and 16 451 new users of metformin and sulfonylureas, respectively. Mean age was 66.4±8.2 years (48% male, 83% Caucasian). Over the 5-year follow-up, 3207 patients developed all-cause dementia (2256 (2.3%) metformin, 951 (5.8%) sulfonylurea users) and 760 patients developed PD (625 (0.7%) metformin, 135 (0.8%) sulfonylurea users). After IPTW, HRs for all-cause dementia and PD were 0.80 (95% CI 0.73 to 0.88) and 1.00 (95% CI 0.79 to 1.28). HRs for AD, VD and MCI were 0.81 (0.70-0.94), 0.79 (0.63-1.00) and 0.91 (0.79-1.04). Stronger associations were observed in patients who were younger (<75 years old), Caucasian, and with moderate renal function. CONCLUSIONS: Metformin users compared with sulfonylurea users were associated with a lower risk of all-cause dementia, AD and VD but not with PD or MCI. Age and renal function modified risk reduction. Our findings support the hypothesis that metformin provides more neuroprotection for dementia than sulfonylureas but not for PD, but f
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- 2022
18. Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials
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van Eijk, Ruben P.A., Jones, Ashley R., Sproviero, William, Shatunov, Aleksey, Shaw, Pamela J., Leigh, P. Nigel, Young, Carolyn A., Shaw, Christopher E., Mora, Gabriele, Mandrioli, Jessica, Borghero, Giuseppe, Volanti, Paolo, Diekstra, Frank P., van Rheenen, Wouter, Verstraete, Esther, Eijkemans, Marinus J.C., Veldink, Jan H., Chio, Adriano, Al-Chalabi, Ammar, van den Berg, Leonard H., and van Es, Michael A.
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- 2017
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19. The relationship between isolated hypertension with brain volumes in UK Biobank
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Newby, Danielle, primary, Winchester, Laura, additional, Sproviero, William, additional, Fernandes, Marco, additional, Ghose, Upamanyu, additional, Lyall, Donald, additional, Launer, Lenore J., additional, and Nevado‐Holgado, Alejo J., additional
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- 2022
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20. Longitudinal analysis of UK Biobank participants suggests age and APOE-dependent alterations of energy metabolism in development of dementia
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Liu, Jun, primary, Amin, Najaf, additional, Sproviero, William, additional, Arnold, Matthias, additional, Batra, Richa, additional, Bonnechere, Bruno, additional, Chiou, Yu-Jie, additional, Fernandes, Marco, additional, Krumsiek, Jan, additional, Newby, Danielle, additional, Nho, Kwangsik, additional, Kim, Jun Pyo, additional, Saykin, Andrew J, additional, Shi, Liu, additional, Winchester, Laura, additional, Yang, Yang, additional, Nevado-Holgado, Alejo J, additional, Kastenmüller, Gabi, additional, Kaddurah-Daouk, Rima F, additional, and van Duijn, Cornelia M, additional
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- 2022
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21. ATXN2 trinucleotide repeat length correlates with risk of ALS
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Sproviero, William, Shatunov, Aleksey, Stahl, Daniel, Shoai, Maryam, van Rheenen, Wouter, Jones, Ashley R., Al-Sarraj, Safa, Andersen, Peter M., Bonini, Nancy M., Conforti, Francesca L., Van Damme, Philip, Daoud, Hussein, Del Mar Amador, Maria, Fogh, Isabella, Forzan, Monica, Gaastra, Ben, Gellera, Cinzia, Gitler, Aaron D., Hardy, John, Fratta, Pietro, La Bella, Vincenzo, Le Ber, Isabelle, Van Langenhove, Tim, Lattante, Serena, Lee, Yi-Chung, Malaspina, Andrea, Meininger, Vincent, Millecamps, Stéphanie, Orrell, Richard, Rademakers, Rosa, Robberecht, Wim, Rouleau, Guy, Ross, Owen A., Salachas, Francois, Sidle, Katie, Smith, Bradley N., Soong, Bing-Wen, Sorarù, Gianni, Stevanin, Giovanni, Kabashi, Edor, Troakes, Claire, van Broeckhoven, Christine, Veldink, Jan H., van den Berg, Leonard H., Shaw, Christopher E., Powell, John F., and Al-Chalabi, Ammar
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- 2017
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22. The association between isolated hypertension and brain volumes in UK Biobank
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Newby, Danielle, primary, Winchester, Laura M, additional, Sproviero, William, additional, Fernandes, Marco, additional, Ghose, Upamanyu, additional, Li, Qingqin S, additional, Launer, Lenore J, additional, and Nevado‐Holgado, Alejo J, additional
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- 2021
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23. Associations Between Brain Volumes and Cognitive Tests with Hypertensive Burden in UK Biobank
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Newby, Danielle, primary, Winchester, Laura, additional, Sproviero, William, additional, Fernandes, Marco, additional, Wang, Dai, additional, Kormilitzin, Andrey, additional, Launer, Lenore J., additional, and Nevado-Holgado, Alejo J., additional
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- 2021
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24. The Relationship Between Isolated Hypertension with Brain Volumes in UK Biobank
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Newby, Danielle, primary, Winchester, Laura, additional, Sproviero, William, additional, Fernandes, Marco, additional, Ghose, Upamanyu, additional, Lyall, Donald, additional, Launer, Lenore, additional, and Nevado-Holgado, Alejo J., additional
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- 2021
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25. A novel NF1 gene mutation in an Italian family with neurofibromatosis type 1
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Gabriele, Anna Lia, Ruggieri, Martino, Patitucci, Alessandra, Magariello, Angela, Conforti, Francesca Luisa, Mazzei, Rosalucia, Muglia, Maria, Ungaro, Carmine, Di Palma, Gemma, Citrigno, Luigi, Sproviero, William, Gambardella, Antonio, and Quattrone, Aldo
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- 2011
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26. Genetic counselling in ALS: facts, uncertainties and clinical suggestions
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Chiò, Adriano, Battistini, Stefania, Calvo, Andrea, Caponnetto, Claudia, Conforti, Francesca L, Corbo, Massimo, Giannini, Fabio, Mandrioli, Jessica, Mora, Gabriele, Sabatelli, Mario, Monsurrò, Maria Rosaria, Tedeschi, Gioacchino, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Volanti, Paolo, Marinou, Kalliopi, Papetti, Laura, Lunetta, Christian, Pintor, Giuseppe Lauria, Salvi, Fabrizio, Bartolomei, Ilaria, Quattrone, Aldo, Gambardella, Antonio, Logroscino, Giancarlo, Simone, Isabella, Pisano, Fabrizio, Spataro, Rossella, La Bella, Vincenzo, Colletti, Tiziana, Mancardi, Gianluigi, Origone, Paola, Sola, Patrizia, Borghero, Giuseppe, Marrosu, Francesco, Marrosu, Maria Giovanna, Murru, Maria Rita, Floris, Gianluca, Cannas, Antonino, Piras, Valeria, Costantino, Emanuela, Pani, Carla, Sotgiu, Maria Alessandra, Pugliatti, Maura, Parish, Leslie D., Cossu, Paola, Ticca, Anna, Rodolico, Carmelo, Portaro, Simona, Ricci, Claudia, Moglia, Cristina, Ossola, Irene, Brunetti, Maura, Barberis, Marco, Canosa, Antonio, Cammarosano, Stefania, Bertuzzo, Davide, Fuda, Giuseppe, Ilardi, Antonio, Manera, Umberto, Pastore, Ilaria, Sproviero, William, Logullo, Francesco, Tanel, Raffaella, Ajmone, Clara, Mastro, Enza, Pain, Debora, Mandich, Paola, Penco, Silvana, Restagno, Gabriella, Zollino, Marcella, and Surbone, Antonella
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- 2014
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27. High Blood Pressure and Risk of Dementia: A Two-Sample Mendelian Randomization Study in the UK Biobank
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Sproviero, William, primary, Winchester, Laura, additional, Newby, Danielle, additional, Fernandes, Marco, additional, Shi, Liu, additional, Goodday, Sarah M., additional, Prats-Uribe, Albert, additional, Alhambra, Daniel P., additional, Buckley, Noel J., additional, and Nevado-Holgado, Alejo J., additional
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- 2021
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28. ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization
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Tazelaar, Gijs, Boeynaems, Steven, De Decker, Mathias, van Vugt, Joke, Kool, Lindy, Goedee, H Stephan, Mclaughlin, Russell, Sproviero, William, Iacoangeli, Alfredo, Moisse, Matthieu, Jacquemyn, Maarten, Daelemans, Dirk, Dekker, Annelot, van der Spek, Rick, Westeneng, Henk-Jan, Kenna, Kevin, Assialioui, Abdelilah, Da Silva, Nica, Millecamps, Stéphanie, Akçimen, Fulya, Al Khleifat, Ahmad, Al-Chalabi, Ammar, Andersen, Peter, Basak, A Nazli, Bauer, Denis, Blair, Ian, Brands, William, Byrne, Ross, Calvo, Andrea, Gonzalez, Yolanda Campos, Chio, Adriano, Cooper-Knock, Jonothan, Corcia, Philippe, Couratier, Philippe, De Carvalho, Mamede, Drory, Vivian, Eitan, Chen, Redondo, Alberto Garcia, Gellera, Cinzia, Glass, Jonathan, Gotkine, Marc, Hardiman, Orla, Hornstein, Eran, Kenna, Brandon, Kiernan, Matthew, Kocoglu, Cemile, Kooyman, Maarten, Landers, John, Alonso, Victoria López, Middelkoop, Bas, Mill, Jonathan, Mitne-Neto, Miguel, Mora Pardina, Jesus, Morrison, Karen, Pinto, Susana, Gromicho, Marta, Panadés, Monica Povedano, Pulit, Sara, Ratti, Antonia, Robberecht, Wim, Schellevis, Raymond, Shatunov, Aleksey, Shaw, Christopher, Shaw, Pamela, Silani, Vincenzo, Staiger, Christine, Ticozzi, Nicola, Tunca, Ceren, Twine, Nathalie, Van Damme, Philip, van den Berg, Leonard, van Doormaal, Perry, van Eijk, Kristel, van Es, Michael, van Rheenen, Wouter, Veldink, Jan, Visscher, Peter, Vourc’h, Patrick, Weber, Markus, Williams, Kelly, Wray, Naomi, Yang, Jian, Zatz, Mayana, Zhang, Katharine, Povedano, Mónica, Pardina, Jesus, Salachas, François, Pasterkamp, R Jeroen, Van Den Bosch, Ludo, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Spinocerebellar Ataxia Type 1 ,amyotrophic lateral sclerosis ,Protein TDP-43 ,Disease Association ,Biology ,[SCCO]Cognitive science ,03 medical and health sciences ,0302 clinical medicine ,C9orf72 ,medicine ,Genetics ,trinucleotide repeat expansions ,Amyotrophic lateral sclerosis ,ComputingMilieux_MISCELLANEOUS ,AcademicSubjects/SCI01870 ,[SCCO.NEUR]Cognitive science/Neuroscience ,General Engineering ,DNA Repeat Expansion ,medicine.disease ,Phenotype ,030104 developmental biology ,DNA repeat expansion ,genetic association study ,Original Article ,AcademicSubjects/MED00310 ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery ,Esclerosi lateral amiotròfica ,Genètica - Abstract
Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10−7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis., Repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. This study shows a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis, possibly via mislocalization of TDP-43, further emphasizing the role of polyglutamine expansions in the pathophysiology of amyotrophic lateral sclerosis., Graphical Abstract Graphical Abstract
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- 2020
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29. Lipidomic traits of plasma and cerebrospinal fluid in amyotrophic lateral sclerosis correlate with disease progression
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Sol, Joaquim, primary, Jové, Mariona, additional, Povedano, Monica, additional, Sproviero, William, additional, Domínguez, Raul, additional, Piñol-Ripoll, Gerard, additional, Romero-Guevara, Ricardo, additional, Hye, Abdul, additional, Al-Chalabi, Ammar, additional, Torres, Pascual, additional, Andres-Benito, Pol, additional, Area-Gómez, Estela, additional, Pamplona, Reinald, additional, Ferrer, Isidro, additional, Ayala, Victòria, additional, and Portero-Otín, Manuel, additional
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- 2021
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30. Development and validation of patient-level prediction models for adverse outcomes following total knee arthroplasty
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Williams, Ross, primary, Reps, Jenna, additional, Sena, Anthony, additional, Burn, Edward, additional, Ying, Helen, additional, Morales, Daniel, additional, Culliford, David, additional, Yu, Dahai, additional, Strauss, Victoria, additional, Duarte-Salles, Talita, additional, Prats-Uribe, Albert, additional, Delmestri, Antonella, additional, Weaver, James, additional, Sproviero, William, additional, Robinson, Danielle, additional, Morgan-Stewart, Henry, additional, Birlie, Belay, additional, Pinedo-Villanueva, Rafael, additional, Kolovos, Spyros, additional, John, Luis, additional, Costello, Ruth, additional, van Speybroeck, Michel, additional, O'Leary, Caroline, additional, Minty, Evan, additional, Falconer, Thomas, additional, Bourke, Alison, additional, Pfohl, Stephen, additional, Burkard, Theresa, additional, Lane, Jennifer, additional, Rijnbeek, Peter, additional, Ryan, Patrick, additional, and Prieto-Alhambra, Daniel, additional
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- 2020
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31. Teaching old drugs new tricks: Do cardiovascular medications effect cognitive decline?
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Newby, Danielle, primary, Winchester, Laura, additional, Sproviero, William, additional, Fernandes, Marco, additional, Launer, Lenore J., additional, Lovestone, Simon, additional, and Nevado‐Holgado, Alejo J, additional
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- 2020
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32. THE p.ARG416CYS MUTATION IN SPG3A GENE ASSOCIATED WITH A PURE FORM OF SPASTIC PARAPLEGIA
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Magariello, Angela, Tortorella, Carla, Citrigno, Luigi, Patitucci, Alessandra, Tortelli, Rosanna, Mazzei, Rosalucia, Conforti, Francesca Luisa, Ungaro, Carmine, Sproviero, William, Gambardella, Antonio, and Muglia, Maria
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- 2012
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33. Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics
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Iacoangeli, Alfredo, primary, Lin, Tian, additional, Al Khleifat, Ahmad, additional, Jones, Ashley R., additional, Opie-Martin, Sarah, additional, Coleman, Jonathan R.I., additional, Shatunov, Aleksey, additional, Sproviero, William, additional, Williams, Kelly L., additional, Garton, Fleur, additional, Restuadi, Restuadi, additional, Henders, Anjali K., additional, Mather, Karen A., additional, Needham, Merilee, additional, Mathers, Susan, additional, Nicholson, Garth A., additional, Rowe, Dominic B., additional, Henderson, Robert, additional, McCombe, Pamela A., additional, Pamphlett, Roger, additional, Blair, Ian P., additional, Schultz, David, additional, Sachdev, Perminder S., additional, Newhouse, Stephen J., additional, Proitsi, Petroula, additional, Fogh, Isabella, additional, Ngo, Shyuan T., additional, Dobson, Richard J.B., additional, Wray, Naomi R., additional, Steyn, Frederik J., additional, and Al-Chalabi, Ammar, additional
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- 2020
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34. Additional file 1: of C9orf72 intermediate expansions of 24â 30 repeats are associated with ALS
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Iacoangeli, Alfredo, Khleifat, Ahmad, Jones, Ashley, Sproviero, William, Shatunov, Aleksey, Opie-Martin, Sarah, Morrison, Karen, Shaw, Pamela, Shaw, Christopher, Fogh, Isabella, Dobson, Richard, Newhouse, Stephen, and Al-Chalabi, Ammar
- Abstract
Figure S1. Bias detection in the meta-analysis: A) Egger test; B) Begg test. C) Funnel plot of the 5 studies used in our meta analysis. Table S1. C9orf72 expansion analysis results obtained with ExpansionHunter on the British/ADNI dataset. Table S2. Pooled odds ratios by omitting one study per iteration. Demographic table. (DOCX 3047 kb)
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- 2019
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35. Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat
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Jones, Ashley R., Woollacott, Ione, Shatunov, Aleksey, Cooper-Knock, Johnathan, Buchman, Vladimir, Sproviero, William, Smith, Bradley, Scott, Kirsten M., Balendra, Rubika, Abel, Olubunmi, McGuffin, Peter, Ellis, Catherine M., Shaw, Pamela J., Morrison, Karen E., Farmer, Anne, Lewis, Cathryn M., Leigh, P. Nigel, Shaw, Christopher E., Powell, John F., and Al-Chalabi, Ammar
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- 2013
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36. Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort
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Tazelaar, Gijs H. P., Dekker, Annelot M., van Vugt, Joke J. F. A., van der Spek, Rick A., Westeneng, Henk-Jan, Kool, Lindy J. B. G., Kenna, Kevin P., van Rheenen, Wouter, Pulit, Sara L., McLaughlin, Russell L., Sproviero, William, Iacoangeli, Alfredo, Huebers, Annemarie, Brenner, David, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Povedano Panades, Monica, Mora Pardina, Jesus S., Glass, Jonathan D., Hardiman, Orla, Al-Chalabi, Ammar, van Damme, Philip, Robberecht, Wim, Landers, John E., Ludolph, Albert C., Weishaupt, Jochen H., van den Berg, Leonard H., Veldink, Jan H., van Es, Michael A., Tazelaar, Gijs H. P., Dekker, Annelot M., van Vugt, Joke J. F. A., van der Spek, Rick A., Westeneng, Henk-Jan, Kool, Lindy J. B. G., Kenna, Kevin P., van Rheenen, Wouter, Pulit, Sara L., McLaughlin, Russell L., Sproviero, William, Iacoangeli, Alfredo, Huebers, Annemarie, Brenner, David, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Povedano Panades, Monica, Mora Pardina, Jesus S., Glass, Jonathan D., Hardiman, Orla, Al-Chalabi, Ammar, van Damme, Philip, Robberecht, Wim, Landers, John E., Ludolph, Albert C., Weishaupt, Jochen H., van den Berg, Leonard H., Veldink, Jan H., and van Es, Michael A.
- Abstract
NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10−5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.
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- 2019
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37. Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort
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Tazelaar, Gijs H P, Dekker, Annelot M, van Vugt, Joke J F A, van der Spek, Rick A, Westeneng, Henk-Jan, Kool, Lindy J B G, Kenna, Kevin P, van Rheenen, Wouter, Pulit, Sara L, McLaughlin, Russell L, Sproviero, William, Iacoangeli, Alfredo, Hübers, Annemarie, Brenner, David, Morrison, Karen E, Shaw, Pamela J, Shaw, Christopher E, Panadés, Monica Povedano, Mora Pardina, Jesus S, Glass, Jonathan D, Hardiman, Orla, Al-Chalabi, Ammar, van Damme, Philip, Robberecht, Wim, Landers, John E, Ludolph, Albert C, Weishaupt, Jochen H, van den Berg, Leonard H, Veldink, Jan H, van Es, Michael A, Project MinE ALS Sequencing Consortium, Tazelaar, Gijs H P, Dekker, Annelot M, van Vugt, Joke J F A, van der Spek, Rick A, Westeneng, Henk-Jan, Kool, Lindy J B G, Kenna, Kevin P, van Rheenen, Wouter, Pulit, Sara L, McLaughlin, Russell L, Sproviero, William, Iacoangeli, Alfredo, Hübers, Annemarie, Brenner, David, Morrison, Karen E, Shaw, Pamela J, Shaw, Christopher E, Panadés, Monica Povedano, Mora Pardina, Jesus S, Glass, Jonathan D, Hardiman, Orla, Al-Chalabi, Ammar, van Damme, Philip, Robberecht, Wim, Landers, John E, Ludolph, Albert C, Weishaupt, Jochen H, van den Berg, Leonard H, Veldink, Jan H, van Es, Michael A, and Project MinE ALS Sequencing Consortium
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- 2019
38. Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort
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Neurogenetica, Brain, Opleiding Neurologie, Projectafdeling ALS, Circulatory Health, ZL Neuromusculaire Ziekten Medisch, Regenerative Medicine and Stem Cells, Tazelaar, Gijs H P, Dekker, Annelot M, van Vugt, Joke J F A, van der Spek, Rick A, Westeneng, Henk-Jan, Kool, Lindy J B G, Kenna, Kevin P, van Rheenen, Wouter, Pulit, Sara L, McLaughlin, Russell L, Sproviero, William, Iacoangeli, Alfredo, Hübers, Annemarie, Brenner, David, Morrison, Karen E, Shaw, Pamela J, Shaw, Christopher E, Panadés, Monica Povedano, Mora Pardina, Jesus S, Glass, Jonathan D, Hardiman, Orla, Al-Chalabi, Ammar, van Damme, Philip, Robberecht, Wim, Landers, John E, Ludolph, Albert C, Weishaupt, Jochen H, van den Berg, Leonard H, Veldink, Jan H, van Es, Michael A, Project MinE ALS Sequencing Consortium, Neurogenetica, Brain, Opleiding Neurologie, Projectafdeling ALS, Circulatory Health, ZL Neuromusculaire Ziekten Medisch, Regenerative Medicine and Stem Cells, Tazelaar, Gijs H P, Dekker, Annelot M, van Vugt, Joke J F A, van der Spek, Rick A, Westeneng, Henk-Jan, Kool, Lindy J B G, Kenna, Kevin P, van Rheenen, Wouter, Pulit, Sara L, McLaughlin, Russell L, Sproviero, William, Iacoangeli, Alfredo, Hübers, Annemarie, Brenner, David, Morrison, Karen E, Shaw, Pamela J, Shaw, Christopher E, Panadés, Monica Povedano, Mora Pardina, Jesus S, Glass, Jonathan D, Hardiman, Orla, Al-Chalabi, Ammar, van Damme, Philip, Robberecht, Wim, Landers, John E, Ludolph, Albert C, Weishaupt, Jochen H, van den Berg, Leonard H, Veldink, Jan H, van Es, Michael A, and Project MinE ALS Sequencing Consortium
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- 2019
39. FUS mutations in sporadic amyotrophic lateral sclerosis: Clinical and genetic analysis
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Sproviero, William, La Bella, Vincenzo, Mazzei, Rosalucia, Valentino, Paola, Rodolico, Carmelo, Simone, Isabella Laura, Logroscino, Giancarlo, Ungaro, Carmine, Magariello, Angela, Patitucci, Alessandra, Tedeschi, Gioacchino, Spataro, Rossella, Condino, Francesca, Bono, Francesco, Citrigno, Luigi, Monsurrò, Maria Rosaria, Muglia, Maria, Gambardella, Antonio, Quattrone, Aldo, and Conforti, Francesca Luisa
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- 2012
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40. Identification of new risk factors for rolandic epilepsy:CNV at Xp22.31 and alterations at cholinergic synapses
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Addis, Laura, Sproviero, William, Thomas, Sanjeev V., Caraballo, Roberto H., Newhouse, Stephen J., Gomez, Kumudini, Hughes, Elaine, Kinali, Maria, McCormick, David, Hannan, Siobhan, Cossu, Silvia, Taylor, Jacqueline, Akman, Cigdem I., Wolf, Steven M., Mandelbaum, David E., Gupta, Rajesh, Van Der Spek, Rick A., Pruna, Dario, and Pal, Deb K.
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epilepsy and seizures ,genome-wide ,copy-number ,developmental - Abstract
Background: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. Objective: To identify rare, causal CNV in patients with RE. Methods: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. Results: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. Conclusion: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.
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- 2018
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41. Telomere length is greater in ALS than in controls: a whole genome sequencing study
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Al Khleifat, Ahmad, primary, Iacoangeli, Alfredo, additional, Shatunov, Aleksey, additional, Fang, Ton, additional, Sproviero, William, additional, Jones, Ashley R., additional, Opie-Martin, Sarah, additional, Morrison, Karen E., additional, Shaw, Pamela J., additional, Shaw, Christopher E., additional, Powell, John F., additional, Dobson, Richard, additional, Newhouse, Steven J., additional, and Al-Chalabi, Ammar, additional
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- 2019
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42. ALSgeneScanner: a pipeline for the analysis and interpretation of DNA sequencing data of ALS patients
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Iacoangeli, Alfredo, primary, Al Khleifat, Ahmad, additional, Sproviero, William, additional, Shatunov, Aleksey, additional, Jones, Ashley R., additional, Opie-Martin, Sarah, additional, Naselli, Ersilia, additional, Topp, Simon D., additional, Fogh, Isabella, additional, Hodges, Angela, additional, Dobson, Richard J., additional, Newhouse, Stephen J., additional, and Al-Chalabi, Ammar, additional
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- 2019
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43. The multistep hypothesis of ALS revisited: The role of genetic mutations
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Chiò, Adriano, Mazzini, Letizia, D'Alfonso, Sandra, Corrado, Lucia, Canosa, Antonio, Moglia, Cristina, Manera, Umberto, Bersano, Enrica, Brunetti, Maura, Barberis, Marco, Veldink, Jan H, van den Berg, Leonard H, Pearce, Neil, Sproviero, William, Mclaughlin, Russell, Vajda, Alice, Hardiman, Orla, Rooney, James, Mora, Gabriele, Calvo, Andrea, and Al-Chalabi, Ammar
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Adult ,Male ,C9orf72 Protein ,Incidence ,Amyotrophic Lateral Sclerosis ,Middle Aged ,Article ,DNA-Binding Proteins ,Superoxide Dismutase-1 ,Mutation ,Humans ,RNA-Binding Protein FUS ,Female ,Genetic Predisposition to Disease ,Genetic Testing ,Aged ,Retrospective Studies - Abstract
OBJECTIVE: Amyotrophic lateral sclerosis (ALS) incidence rates are consistent with the hypothesis that ALS is a multistep process. We tested the hypothesis that carrying a large effect mutation might account for ≥1 steps through the effect of the mutation, thus leaving fewer remaining steps before ALS begins. METHODS: We generated incidence data from an ALS population register in Italy (2007-2015) for which genetic analysis for C9orf72, SOD1, TARDBP, and FUS genes was performed in 82% of incident cases. As confirmation, we used data from ALS cases diagnosed in the Republic of Ireland (2006-2014). We regressed the log of age-specific incidence against the log of age with least-squares regression for the subpopulation carrying disease-associated variation in each separate gene. RESULTS: Of the 1,077 genetically tested cases, 74 (6.9%) carried C9orf72 mutations, 20 (1.9%) had SOD1 mutations, 15 (1.4%) had TARDBP mutations, and 3 (0.3%) carried FUS mutations. In the whole population, there was a linear relationship between log incidence and log age (r2 = 0.98) with a slope estimate of 4.65 (4.37-4.95), consistent with a 6-step process. The analysis for C9orf72-mutated patients confirmed a linear relationship (r2 = 0.94) with a slope estimate of 2.22 (1.74-2.29), suggesting a 3-step process. This estimate was confirmed by data from the Irish ALS register. The slope estimate was consistent with a 2-step process for SOD1 and with a 4-step process for TARDBP. CONCLUSION: The identification of a reduced number of steps in patients with ALS with genetic mutations compared to those without mutations supports the idea of ALS as a multistep process and is an important advance for dissecting the pathogenic process in ALS.
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- 2017
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44. Project MinE : study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis
- Author
-
Project Mine Als Sequencing Consortium, Mine Als Sequencing Consortium, Pulit, Sara L., Dekker, Annelot M., Al Khleifat, Ahmad, Brands, William J., Iacoangeli, Alfredo, Kenna, Kevin P., Kavak, Ersen, Kooyman, Maarten, McLaughlin, Russell L., Middelkoop, Bas, Moisse, Matthieu, Schellevis, Raymond D., Shatunov, Aleksey, Sproviero, William, Tazelaar, Gijs H.P., van der Spek, Rick A.A., van Doormaal, Perry T.C., van Eijk, Kristel R., van Vugt, Joke, Basak, A. Nazli, Blair, Ian P., Glass, Jonathan D., Hardiman, Orla, Hide, Winston, Landers, John E., Mora, Jesus S., Morrison, Karen E., Newhouse, Stephen, Robberecht, Wim, Shaw, Christopher E., Shaw, Pamela J., van Damme, Philip, van Es, Michael A., Wray, Naomi R., Al-Chalabi, Ammar, van Den Berg, Leonard H., Veldink, Jan H., Project Mine Als Sequencing Consortium, Mine Als Sequencing Consortium, Pulit, Sara L., Dekker, Annelot M., Al Khleifat, Ahmad, Brands, William J., Iacoangeli, Alfredo, Kenna, Kevin P., Kavak, Ersen, Kooyman, Maarten, McLaughlin, Russell L., Middelkoop, Bas, Moisse, Matthieu, Schellevis, Raymond D., Shatunov, Aleksey, Sproviero, William, Tazelaar, Gijs H.P., van der Spek, Rick A.A., van Doormaal, Perry T.C., van Eijk, Kristel R., van Vugt, Joke, Basak, A. Nazli, Blair, Ian P., Glass, Jonathan D., Hardiman, Orla, Hide, Winston, Landers, John E., Mora, Jesus S., Morrison, Karen E., Newhouse, Stephen, Robberecht, Wim, Shaw, Christopher E., Shaw, Pamela J., van Damme, Philip, van Es, Michael A., Wray, Naomi R., Al-Chalabi, Ammar, van Den Berg, Leonard H., and Veldink, Jan H.
- Published
- 2018
45. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- Author
-
Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick, Pliner, Hannah A., Shankaracharya, null, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Mazzini, Letizia, Messina, Sonia, D'Alfonso, Sandra, Corrado, Lucia, Ferrucci, Luigi, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, George, Appel, Stanley, Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard S., Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Allen, Andrew S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steven, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Wyman, Stacia K., Van Eyk, Jennifer E., Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L. M. A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Mattieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Basak, A. Nazli, Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Esteban-Pérez, Jesús, García-Redondo, Alberto, Al-Chalabi, Ammar, Al Kheifat, Ahmad, Andersen, Peter, Chio, Adriano, Cooper-Knock, Jonathan, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Landers, John, McLaughlin, Russell, Mill, Jonathan, Neto, Miguel Mitne, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van Eijk, Kristel, van Es, Michael, van Vugt, Joke, Veldink, Jan, Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Rogaeva, Ekaterina, Zinman, Lorne, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., Landers, John E., Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick, Pliner, Hannah A., Shankaracharya, null, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Mazzini, Letizia, Messina, Sonia, D'Alfonso, Sandra, Corrado, Lucia, Ferrucci, Luigi, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, George, Appel, Stanley, Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard S., Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Allen, Andrew S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steven, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Wyman, Stacia K., Van Eyk, Jennifer E., Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L. M. A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Mattieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Basak, A. Nazli, Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Esteban-Pérez, Jesús, García-Redondo, Alberto, Al-Chalabi, Ammar, Al Kheifat, Ahmad, Andersen, Peter, Chio, Adriano, Cooper-Knock, Jonathan, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Landers, John, McLaughlin, Russell, Mill, Jonathan, Neto, Miguel Mitne, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van Eijk, Kristel, van Es, Michael, van Vugt, Joke, Veldink, Jan, Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Rogaeva, Ekaterina, Zinman, Lorne, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.
- Abstract
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.
- Published
- 2018
46. Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis
- Author
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CMM Groep De Ridder, Circulatory Health, Opleiding Neurologie, Neurogenetica, Projectafdeling ALS, Brain, ZL Neuromusculaire Ziekten Medisch, Regenerative Medicine and Stem Cells, Project Mine Als Sequencing Consortium, Mine Als Sequencing Consortium, Pulit, Sara L., Dekker, Annelot M., Al Khleifat, Ahmad, Brands, William J., Iacoangeli, Alfredo, Kenna, Kevin P., Kavak, Ersen, Kooyman, Maarten, McLaughlin, Russell L., Middelkoop, Bas, Moisse, Matthieu, Schellevis, Raymond D., Shatunov, Aleksey, Sproviero, William, Tazelaar, Gijs H.P., van der Spek, Rick A.A., van Doormaal, Perry T.C., van Eijk, Kristel R., van Vugt, Joke, Basak, A. Nazli, Blair, Ian P., Glass, Jonathan D., Hardiman, Orla, Hide, Winston, Landers, John E., Mora, Jesus S., Morrison, Karen E., Newhouse, Stephen, Robberecht, Wim, Shaw, Christopher E., Shaw, Pamela J., van Damme, Philip, van Es, Michael A., Wray, Naomi R., Al-Chalabi, Ammar, van Den Berg, Leonard H., Veldink, Jan H., CMM Groep De Ridder, Circulatory Health, Opleiding Neurologie, Neurogenetica, Projectafdeling ALS, Brain, ZL Neuromusculaire Ziekten Medisch, Regenerative Medicine and Stem Cells, Project Mine Als Sequencing Consortium, Mine Als Sequencing Consortium, Pulit, Sara L., Dekker, Annelot M., Al Khleifat, Ahmad, Brands, William J., Iacoangeli, Alfredo, Kenna, Kevin P., Kavak, Ersen, Kooyman, Maarten, McLaughlin, Russell L., Middelkoop, Bas, Moisse, Matthieu, Schellevis, Raymond D., Shatunov, Aleksey, Sproviero, William, Tazelaar, Gijs H.P., van der Spek, Rick A.A., van Doormaal, Perry T.C., van Eijk, Kristel R., van Vugt, Joke, Basak, A. Nazli, Blair, Ian P., Glass, Jonathan D., Hardiman, Orla, Hide, Winston, Landers, John E., Mora, Jesus S., Morrison, Karen E., Newhouse, Stephen, Robberecht, Wim, Shaw, Christopher E., Shaw, Pamela J., van Damme, Philip, van Es, Michael A., Wray, Naomi R., Al-Chalabi, Ammar, van Den Berg, Leonard H., and Veldink, Jan H.
- Published
- 2018
47. Targeted genetic screen in amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype
- Author
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Cooper-Knock, Johnathan, Robins, Henry, Niedermoser, Isabell, Wyles, Matthew, Heath, Paul R., Higginbottom, Adrian, Walsh, Theresa, Kazoka, Mbombe, Al Kheifat, Ahmad, Al-Chalabi, Ammar, Basak, Nazli, Blair, Ian, Dekker, Annelot, Hardiman, Orla, Hide, Winston, Iacoangeli, Alfredo, Kenna, Kevin, Landers, John, McLaughlin, Russel, Mill, Jonathan, Middelkoop, Bas, Moisse, Mattieu, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pulit, Sara, Shatunov, Aleksey, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van der Spek, Rick, Eijk, Kristelvan, van Es, Michael, van Rheenen, Wouter, van Vugt, Joke, Veldink, Jan, Kooyman, Maarten, Glass, Jonathan, Robberecht, Wim, Gotkine, Marc, Drory, Vivian, Kiernan, Matthew, Neto, Miguel Mitne, Ztaz, Mayana, Couratier, Philippe, Corcia, Philippe, Silani, Vincenzo, and Chio, Adriano
- Subjects
Oligogenic inheritance ,Cellular and Molecular Neuroscience ,C9ORF72 ,DNA sequencing ,RNA binding proteins ,Amyotrophic lateral sclerosis ,Molecular Biology - Abstract
Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.
- Published
- 2017
48. Detection of long repeat expansions from PCR-free whole-genome sequence data
- Author
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Dolzhenko, Egor, van Vugt, Joke J.F.A., Shaw, Richard J., Bekritsky, Mitchell A., van Blitterswijk, Marka, Narzisi, Giuseppe, Ajay, Subramanian S., Rajan, Vani, Kingsbury, Zoya, Humphray, Sean J., Schellevis, Raymond D., Brands, William J., Baker, Matt, Rademakers, Rosa, Kooyman, Maarten, Tazelaar, Gijs H.P., van Es, Michael A., McLaughlin, Russell, Sproviero, William, Shatunov, Aleksey, Jones, Ashley, Al Khleifat, Ahmad, Pittman, Alan, Morgan, Sarah, Hardiman, Orla, Al-Chalabi, Ammar, Shaw, Chris, Smith, Bradley, Neo, Edmund J., Morrison, Karen, Shaw, Pamela J., Reeves, Catherine, Winterkorn, Lara, Wexler, Nancy S., Housman, David E., Ng, Christopher, Li, Alina, Taft, Ryan J., van den Berg, Leonard H., Bentley, David R., Veldink, Jan H., and Eberle, Michael A.
- Subjects
Whole genome sequencing ,Genetics ,0303 health sciences ,03 medical and health sciences ,0302 clinical medicine ,Locus (genetics) ,Biology ,Trinucleotide repeat expansion ,Genome ,030217 neurology & neurosurgery ,030304 developmental biology ,3. Good health ,Southern blot - Abstract
Identifying large repeat expansions such as those that cause amyotrophic lateral sclerosis (ALS) and Fragile X syndrome is challenging for short-read (100-150 bp) whole genome sequencing (WGS) data. A solution to this problem is an important step towards integrating WGS into precision medicine. We have developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3,001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Taking the RP-PCR calls as the ground truth, our WGS-based method identified pathogenic repeat expansions with 98.1% sensitivity and 99.7% specificity. Further inspection identified that all 11 conflicts were resolved as errors in the original RP-PCR results. Compared against this updated result, ExpansionHunter correctly classified all (212/212) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2,786/2,789) of the wild type samples were correctly classified as wild type by this method with the remaining two identified as possible expansions. We further applied our algorithm to a set of 144 samples where every sample had one of eight different pathogenic repeat expansions including examples associated with fragile X syndrome, Friedreich’s ataxia and Huntington’s disease and correctly flagged all of the known repeat expansions. Finally, we tested the accuracy of our method for short repeats by comparing our genotypes with results from 860 samples sized using fragment length analysis and determined that our calls were >95% accurate. ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
- Published
- 2016
- Full Text
- View/download PDF
49. ALSgeneScanner: a pipeline for the analysis and interpretation of DNA NGS data of ALS patients
- Author
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Iacoangeli, Alfredo, primary, Al Khleifat, Ahmad, additional, Sproviero, William, additional, Shatunov, Aleksey, additional, Jones, Ashley R, additional, Opie-Martin, Sarah, additional, Naselli, Ersilia, additional, Fogh, Isabella, additional, Hodges, Angela, additional, Dobson, Richard J, additional, Newhouse, Stephen J, additional, and Al-Chalabi, Ammar, additional
- Published
- 2018
- Full Text
- View/download PDF
50. Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses
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Addis, Laura, primary, Sproviero, William, additional, Thomas, Sanjeev V, additional, Caraballo, Roberto H, additional, Newhouse, Stephen J, additional, Gomez, Kumudini, additional, Hughes, Elaine, additional, Kinali, Maria, additional, McCormick, David, additional, Hannan, Siobhan, additional, Cossu, Silvia, additional, Taylor, Jacqueline, additional, Akman, Cigdem I, additional, Wolf, Steven M, additional, Mandelbaum, David E, additional, Gupta, Rajesh, additional, van der Spek, Rick A, additional, Pruna, Dario, additional, and Pal, Deb K, additional
- Published
- 2018
- Full Text
- View/download PDF
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