Citations 2
Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Rheenen, Wouter van , Spek, Rick van der, Berg, Leonard van den, Hop, Paul , Zwamborn, Ramona, Klein, Niek de , Westra, Harm-Jan , Bakker, Olivier, Shireby, Gemma , Dolzhenko, Egor, Dekker, Annelot, Westeneng, Henk-Jan, Tazelaar, Gijs, Eijk, Kristel van , Kooyman, Maarten , Doherty, Mark, Iacoangeli, Alfredo, Cooper‐Knock, Johnathan , Smith, Bradley , Chandran, Siddharthan , Morrison, Karen, Shaw, Pamela, Hardy, John , Orrell, Richard, Basak, Nazli, Ratti, Antonia, Pinter, Guiseppe Lauria, D'Alfonso, Sandra, Soraru, Gianni, Padovani, Alessandro , Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Nefussy, Beatrice, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Baloh, Robert, Bell, Shaugn, Vourc'h, Patrick, Corcia, Philippe, Couratier, Philippe, Meininger, Vincent, Salachas, Francois, Pardina, Jesús Mora, Assialioui, Abdelilah , Rojas‐García, Ricardo , Dion, Patrick, Ludolph, Albert, Weishaupt, Jochen, Brenner, David, Freischmidt, Axel , Bensimon, Gilbert , Durr, Alexandra, Payan, Christine, Saker-Delye, Safa, Wood, Nicholas , Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Braun, Alice, Hofman, Albert, Cichon, Sven , Traynor, Bryan, Singleton, Andrew, Neto, Miguel Mitne, Ophoff, Roel, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Rödiger, Annekathrin, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Berjamin, Stubendorff, Beatrice, Witte, Otto W. , Hübner, Christian, Graff, Caroline , Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia , Koritnik, Blaž , Zidar, Janez , Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Mónica, Henderson, Robert , Furlong, Sarah , McCombe, Pamela, Ngo, Shyuan, Steyn, Frederik, Mather, Karen A. , Sachdev, Perminder S. , Henders, Anjali, Carvalho, Mamede de, Petri, Susanne, Weber, Markus , Glass, Jonathan D. , Brown, Robert, Landers, John, Garton, Fleur, McRae, Allan, Mill, Jonathan , Kenna, Kevin, Runz, Heiko, Franke, Lude , Damme, Philip Van , Gaur, Nayana , Steyn, Frederik J. , Landers, John E. , Westra, Harm-Jan , Steyn, F J , Cichon, Sven , Sachdev, Perminder S , Van Damme, Philip , Hardy, John , Padovani, Alessandro , Graff, Caroline , Spek, Rick A. A. van der , Bakker, Mark K. , Veldink, Jan H. , Vugt, Joke J.F.A. van , Zwamborn, Ramona A.J. , Deelen, Patrick , Hannon, Eilís , Moisse, Matthieu , Baird, Denis A. , Restuadi, Restuadi , Gawor, Klara , Westeneng, Henk‐Jan , Byrne, Ross Patrick , Heverin, Mark , Khleifat, Ahmad Al , Iacoangeli, Alfredo , Shatunov, Aleksey , Ticozzi, Nicola , Gromicho, Marta , Pal, Suvankar , Orrell, Richard W., Sendtner, Michael , Meyer, Thomas , Basak, Nazli A., Kooi, Anneke J. van der , Ratti, Antonia , Fogh, Isabella , Gellera, Cinzia , Corti, Stefania Paola , Cereda, Cristina , Sproviero, Daisy , D’Alfonso, Sandra , Siciliano, Gabriele , Filosto, Massimiliano , Chiò, Adriano , Calvo, Andrea , Moglia, Cristina , Brunetti, Maura , Canosa, Antonio , Grassano, Maurizio , Beghi, Ettore , Pupillo, Elisabetta , Logroscino, Giancarlo , Osmanovic, Alma , Nordin, Angelica , Lerner, Yossef, Zabari, Michal, Gotkine, Marc , Vourc’h, Patrick , Corcia, Philippe , Couratier, Philippe , Millecamps, Stéphanie , Meininger, Vincent, Salachas, François, Ross, Jay P. , Ludolph, Albert, Brice, Alexis , Dürr, Alexandra , Saker-Delye, Safaa, Wood, Nicholas , Topp, Simon , Rademakers, Rosa , Tittmann, Lukas , Franke, André , Ripke, Stephan , Braun, Alice , Kraft, Julia , Whiteman, David C. , Olsen, Catherine M. , Uitterlinden, André G. , Hofman, Albert, Rietschel, Marcella , Nöthen, Markus M. , Amouyel, Philippe , Traynor, Bryan J. , Singleton, Andrew, Cauchi, Ruben J. , Ophoff, Roel A. , Lomen‐Hoerth, Catherine , Deerlin, Vivianna M. Van , Großkreutz, Julian , Rödiger, Annekathrin, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Steinbach, Robert , Hübner, Christian, Fominykh, Vera , Demeshonok, Vera, Rogelj, Boris , Drory, Vivian, Blair, Ian P. , Kiernan, Matthew C. , Benyamin, Beben , Mathers, Susan , Needham, Merrilee , Ngo, Shyuan T. , Nicholson, Garth A. , Pamphlett, Roger , Rowe, Dominic B. , Williams, Kelly L. , Wallace, Leanne M. , Carvalho, Mamede A. de , Pinto, Susana , Petri, Susanne , Rouleau, Guy Armand , Silani, Vincenzo , Curtis, Charles J. C. , Breen, Gerome , Brown, Robert, Shaw, Christopher E. , Andersen, Peter Munch , Groen, Ewout J. N. , Es, Michael A. van , Pasterkamp, R. Jeroen , Fan, Dongsheng , Smith, George Davey , Gaunt, Tom R. , Eberle, Michael A. , McLaughlin, Russell L. , Hardiman, Orla , Wray, Naomi , Tsai, Ellen A. , Runz, Heiko , Al‐Chalabi, Ammar
No container title available | March 18, 2021 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
Neuronal intranuclear inclusion disease is genetically heterogeneous
Chen, Zhongbo , Yau, Wai Yan , Tucci, Arianna , Sivakumar, Prasanth, Turner, Chris, Efthymiou, Stéphanie , Ibáñez, Kristina , Sullivan, Roisin , Bibi, Farah , Athanasiou‐Fragkouli, Alkyoni , Bourinaris, Thomas, Révész, Tamás , Lashley, Tammaryn , DeTure, Michael , Josephs, Keith A. , Gelpí, Ellen , Kovács, Gábor G. , Halliday, Glenda M. , Rowe, Dominic B. , Blair, Ian P. , Tienari, Pentti J. , Suomalainen, Anu , Fox, Nick C. , Wood, Nicholas , Haltia, Matti, Hardy, John , Ryten, Mina , Vandrovcová, Jana , Houlden, Henry , Yan Yau, Wai , Sullivan, Roisin , Dickson, Dennis W , Josephs, Keith A , Kovacs, Gabor G , Halliday, Glenda , Hardy, John , Gelpi, Ellen , Fox, Nick C , Houlden, Henry , Vandrovcova, Jana , Jaunmuktane, Zane , Taliun, Sarah A. Gagliano , Zhang, David , Lashley, Tammaryn , Dickson, Dennis W. , Lees, Andrew John , Wood, Nicholas
Annals of Clinical and Translational Neurology | August 10, 2020 | Volume: 7 | Issue: 9 | Pages: 1716-1725
AbstractNeuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico‐based screening using whole‐genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.