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2. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Author

van Rheenen, Wouter, van der Spek, Rick AA, Bakker, Mark K, van Vugt, Joke JFA, Hop, Paul J, Zwamborn, Ramona AJ, de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B, Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M, Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs HP, van Eijk, Kristel R, Kooyman, Maarten, Byrne, Ross P, Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N, Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E, Shaw, Pamela J, Hardy, John, Orrell, Richard W, Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J, Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H, Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S, Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A, Ross, Jay P, Ludolph, Albert C, Weishaupt, Jochen H, Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine AM, Saker-Delye, Safa, Wood, Nicholas W, Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, and Kraft, Julia

Subjects
Human Genome, Neurodegenerative, Clinical Research, Rare Diseases, Prevention, ALS, Neurosciences, Genetics, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Amyotrophic Lateral Sclerosis, Brain, Cholesterol, Disease Progression, Female, Genome-Wide Association Study, Glutamine, Humans, Male, Mendelian Randomization Analysis, Microsatellite Repeats, Mutation, Neurodegenerative Diseases, Neurons, Quantitative Trait Loci, RNA-Seq, Risk Factors, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, SLAP Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

Published
2021

3. Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis

Author

Harvey, Calum, Weinreich, Marcel, Lee, James A.K., Shaw, Allan C., Ferraiuolo, Laura, Mortiboys, Heather, Zhang, Sai, Hop, Paul J., Zwamborn, Ramona A.J., van Eijk, Kristel, Julian, Thomas H., Moll, Tobias, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Quinn, John P., Pfaff, Abigail L., Kõks, Sulev, Poulton, Joanna, Battle, Stephanie L., Arking, Dan E., Snyder, Michael P., Veldink, Jan H., Kenna, Kevin P., Shaw, Pamela J., and Cooper-Knock, Johnathan

Published
2024
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5. Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3′UTR protect against ALS

Author

Eitan, Chen, Siany, Aviad, Barkan, Elad, Olender, Tsviya, van Eijk, Kristel R., Moisse, Matthieu, Farhan, Sali M. K., Danino, Yehuda M., Yanowski, Eran, Marmor-Kollet, Hagai, Rivkin, Natalia, Yacovzada, Nancy Sarah, Hung, Shu-Ting, Cooper-Knock, Johnathan, Yu, Chien-Hsiung, Louis, Cynthia, Masters, Seth L., Kenna, Kevin P., van der Spek, Rick A. A., Sproviero, William, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Jones, Ashley R., Elbaz-Alon, Yael, Cohen, Yahel, Chapnik, Elik, Rothschild, Daphna, Weissbrod, Omer, Beck, Gilad, Ainbinder, Elena, Ben-Dor, Shifra, Werneburg, Sebastian, Schafer, Dorothy P., Brown, Jr, Robert H., Shaw, Pamela J., Van Damme, Philip, van den Berg, Leonard H., Phatnani, Hemali, Segal, Eran, Ichida, Justin K., Al-Chalabi, Ammar, Veldink, Jan H., and Hornstein, Eran

Published
2022
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6. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Author

Al Khleifat, Ahmad, Iacoangeli, Alfredo, van Vugt, Joke J. F. A., Bowles, Harry, Moisse, Matthieu, Zwamborn, Ramona A. J., van der Spek, Rick A. A., Shatunov, Aleksey, Cooper-Knock, Johnathan, Topp, Simon, Byrne, Ross, Gellera, Cinzia, López, Victoria, Jones, Ashley R., Opie-Martin, Sarah, Vural, Atay, Campos, Yolanda, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel R., Kenna, Kevin, Weber, Markus, Smith, Bradley, Fogh, Isabella, Silani, Vincenzo, Morrison, Karen E., Dobson, Richard, van Es, Michael A., McLaughlin, Russell L., Vourc’h, Patrick, Chio, Adriano, Corcia, Philippe, de Carvalho, Mamede, Gotkine, Marc, Panades, Monica P., Mora, Jesus S., Shaw, Pamela J., Landers, John E., Glass, Jonathan D., Shaw, Christopher E., Basak, Nazli, Hardiman, Orla, Robberecht, Wim, Van Damme, Philip, van den Berg, Leonard H., Veldink, Jan H., and Al-Chalabi, Ammar

Published
2022
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7. Deconvolution of polygenic risk score in single cells unravels cellular and molecular heterogeneity of complex human diseases

Author

Zhang, Sai, primary, Shu, Hantao, additional, Zhou, Jingtian, additional, Rubin-Sigler, Jasper, additional, Yang, Xiaoyu, additional, Liu, Yuxi, additional, Cooper-Knock, Johnathan, additional, Monte, Emma, additional, Zhu, Chenchen, additional, Tu, Sharon, additional, Li, Han, additional, Tong, Mingming, additional, Ecker, Joseph, additional, Ichida, Justin, additional, Shen, Yin, additional, Zeng, Jianyang, additional, Tsao, Philip, additional, and Snyder, Michael, additional

Published
2024
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8. Deep learning modeling of rare noncoding genetic variants in human motor neurons definesCCDC146as a therapeutic target for ALS

Author

Zhang, Sai, primary, Moll, Tobias, additional, Rubin-Sigler, Jasper, additional, Tu, Sharon, additional, Li, Shuya, additional, Yuan, Enming, additional, Liu, Menghui, additional, Butt, Afreen, additional, Harvey, Calum, additional, Gornall, Sarah, additional, Alhalthli, Elham, additional, Shaw, Allan, additional, Souza, Cleide Dos Santos, additional, Ferraiuolo, Laura, additional, Hornstein, Eran, additional, Shelkovnikova, Tatyana, additional, van Dijk, Charlotte H., additional, Timpanaro, Ilia S., additional, Kenna, Kevin P., additional, Zeng, Jianyang, additional, Tsao, Philip S., additional, Shaw, Pamela J., additional, Ichida, Justin K., additional, Cooper-Knock, Johnathan, additional, and Snyder, Michael P., additional

Published
2024
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9. Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS

Author

Neurologen, Projectafdeling ALS, Brain, Neurogenetica, Genetic Risks, Marriott, Heather, Spargo, Thomas P, Al Khleifat, Ahmad, Andersen, Peter M, Başak, Nazli A, Cooper-Knock, Johnathan, Corcia, Philippe, Couratier, Philippe, de Carvalho, Mamede, Drory, Vivian, Gotkine, Marc, Landers, John E, McLaughlin, Russell, Pardina, Jesús S Mora, Morrison, Karen E, Pinto, Susana, Shaw, Christopher E, Shaw, Pamela J, Silani, Vincenzo, Ticozzi, Nicola, van Damme, Philip, van den Berg, Leonard H, Vourc'h, Patrick, Weber, Markus, Veldink, Jan H, Dobson, Richard J, Schwab, Patrick, Al-Chalabi, Ammar, Iacoangeli, Alfredo, Project MinE ALS Sequencing Consortium, Neurologen, Projectafdeling ALS, Brain, Neurogenetica, Genetic Risks, Marriott, Heather, Spargo, Thomas P, Al Khleifat, Ahmad, Andersen, Peter M, Başak, Nazli A, Cooper-Knock, Johnathan, Corcia, Philippe, Couratier, Philippe, de Carvalho, Mamede, Drory, Vivian, Gotkine, Marc, Landers, John E, McLaughlin, Russell, Pardina, Jesús S Mora, Morrison, Karen E, Pinto, Susana, Shaw, Christopher E, Shaw, Pamela J, Silani, Vincenzo, Ticozzi, Nicola, van Damme, Philip, van den Berg, Leonard H, Vourc'h, Patrick, Weber, Markus, Veldink, Jan H, Dobson, Richard J, Schwab, Patrick, Al-Chalabi, Ammar, Iacoangeli, Alfredo, and Project MinE ALS Sequencing Consortium

Published
2024

10. Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis

Author

Neurogenetica, Brain, Genetic Risks, Neurologen, Translational Neuroscience, Harvey, Calum, Weinreich, Marcel, Lee, James A.K., Shaw, Allan C., Ferraiuolo, Laura, Mortiboys, Heather, Zhang, Sai, Hop, Paul J., Zwamborn, Ramona A.J., van Eijk, Kristel, Julian, Thomas H., Moll, Tobias, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Quinn, John P., Pfaff, Abigail L., Kõks, Sulev, Poulton, Joanna, Battle, Stephanie L., Arking, Dan E., Snyder, Michael P., Veldink, Jan H., Kenna, Kevin P., Shaw, Pamela J., Cooper-Knock, Johnathan, Project MinE ALS Sequencing Consortium, Neurogenetica, Brain, Genetic Risks, Neurologen, Translational Neuroscience, Harvey, Calum, Weinreich, Marcel, Lee, James A.K., Shaw, Allan C., Ferraiuolo, Laura, Mortiboys, Heather, Zhang, Sai, Hop, Paul J., Zwamborn, Ramona A.J., van Eijk, Kristel, Julian, Thomas H., Moll, Tobias, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Quinn, John P., Pfaff, Abigail L., Kõks, Sulev, Poulton, Joanna, Battle, Stephanie L., Arking, Dan E., Snyder, Michael P., Veldink, Jan H., Kenna, Kevin P., Shaw, Pamela J., Cooper-Knock, Johnathan, and Project MinE ALS Sequencing Consortium

Published
2024

11. Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS

Author

Marriott, Heather, Spargo, Thomas P., Al Khleifat, Ahmad, Andersen, Peter M., Başak, Nazli A., Cooper-Knock, Johnathan, Corcia, Philippe, Couratier, Philippe, de Carvalho, Mamede, Drory, Vivian, Gotkine, Marc, Landers, John E., McLaughlin, Russell, Pardina, Jesús S. Mora, Morrison, Karen E., Pinto, Susana, Shaw, Christopher E., Shaw, Pamela J., Silani, Vincenzo, Ticozzi, Nicola, van Damme, Philip, van den Berg, Leonard H., Vourc'h, Patrick, Weber, Markus, Veldink, Jan H., Dobson, Richard J., Schwab, Patrick, Al-Chalabi, Ammar, Iacoangeli, Alfredo, Marriott, Heather, Spargo, Thomas P., Al Khleifat, Ahmad, Andersen, Peter M., Başak, Nazli A., Cooper-Knock, Johnathan, Corcia, Philippe, Couratier, Philippe, de Carvalho, Mamede, Drory, Vivian, Gotkine, Marc, Landers, John E., McLaughlin, Russell, Pardina, Jesús S. Mora, Morrison, Karen E., Pinto, Susana, Shaw, Christopher E., Shaw, Pamela J., Silani, Vincenzo, Ticozzi, Nicola, van Damme, Philip, van den Berg, Leonard H., Vourc'h, Patrick, Weber, Markus, Veldink, Jan H., Dobson, Richard J., Schwab, Patrick, Al-Chalabi, Ammar, and Iacoangeli, Alfredo

Abstract

Objective: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data. Results: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13–9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14–1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18–1.77, pMadsen–Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86–4.37, pMadsen–Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricated architecture that requires further investigation. Interpretation: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.

Published
2024
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12. TDP-43 is a Master Regulator of Paraspeckle Condensation

Author

Hodgson, Rachel, primary, Huang, Wan-Ping, additional, Kumar, Vedanth, additional, An, Haiyan, additional, Chalakova, Zhaklin, additional, Rayment, Jessica, additional, Ellis, Brittany C.S., additional, Stender, Emil G.P., additional, van Vugt, Joke J.F.A., additional, Sequencing Consortium, Project MinE ALS, additional, Locker, Nicolas, additional, Pitout, Ianthe, additional, Fletcher, Sue, additional, Cooper-Knock, Johnathan, additional, and Shelkovnikova, Tatyana, additional

Published
2024
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15. Author Correction: Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Author

van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Jr., Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.

Published
2022
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16. A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations

Author

Allen, Scott P., primary, Al Sultan, Afnan, additional, Kabucho Kibirige, Elaine, additional, Tonkiss, Erin, additional, Hamer, Keaton J., additional, Castelli, Lydia M., additional, Lin, Ya-Hui, additional, Roscoe, Sarah, additional, Stefanidis, Nikolaos, additional, Mead, Richard J., additional, Highley, J. Robin, additional, Cooper-Knock, Johnathan, additional, Hautbergue, Guillaume M., additional, Heath, Paul R., additional, Kirby, Janine, additional, and Shaw, Pamela J., additional

Published
2023
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18. Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

Author

Adey, Brett N., primary, Cooper-Knock, Johnathan, additional, Al Khleifat, Ahmad, additional, Fogh, Isabella, additional, van Damme, Philip, additional, Corcia, Philippe, additional, Couratier, Philippe, additional, Hardiman, Orla, additional, McLaughlin, Russell, additional, Gotkine, Marc, additional, Drory, Vivian, additional, Silani, Vincenzo, additional, Ticozzi, Nicola, additional, Veldink, Jan H., additional, van den Berg, Leonard H., additional, de Carvalho, Mamede, additional, Pinto, Susana, additional, Mora Pardina, Jesus S., additional, Povedano Panades, Mónica, additional, Andersen, Peter M., additional, Weber, Markus, additional, Başak, Nazli A., additional, Shaw, Christopher E., additional, Shaw, Pamela J., additional, Morrison, Karen E., additional, Landers, John E., additional, Glass, Jonathan D., additional, Vourc’h, Patrick, additional, Dobson, Richard J. B., additional, Breen, Gerome, additional, Al-Chalabi, Ammar, additional, Jones, Ashley R., additional, and Iacoangeli, Alfredo, additional

Published
2023
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19. A cell-penetrant peptide blocking C9ORF72 -repeat RNA nuclear export reduces the neurotoxic effects of dipeptide repeat proteins

Author

Castelli, Lydia M., primary, Lin, Ya-Hui, additional, Sanchez-Martinez, Alvaro, additional, Gül, Aytaç, additional, Mohd Imran, Kamallia, additional, Higginbottom, Adrian, additional, Upadhyay, Santosh Kumar, additional, Márkus, Nóra M., additional, Rua Martins, Raquel, additional, Cooper-Knock, Johnathan, additional, Montmasson, Claire, additional, Cohen, Rebecca, additional, Walton, Amy, additional, Bauer, Claudia S., additional, De Vos, Kurt J., additional, Mead, Richard J., additional, Azzouz, Mimoun, additional, Dominguez, Cyril, additional, Ferraiuolo, Laura, additional, Shaw, Pamela J., additional, Whitworth, Alexander J., additional, and Hautbergue, Guillaume M., additional

Published
2023
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20. Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

Author

Adey, Brett N., Cooper-Knock, Johnathan, Al Khleifat, Ahmad, Fogh, Isabella, van Damme, Philip, Corcia, Philippe, Couratier, Philippe, Hardiman, Orla, McLaughlin, Russell, Gotkine, Marc, Drory, Vivian, Silani, Vincenzo, Ticozzi, Nicola, Veldink, Jan H., van den Berg, Leonard H., de Carvalho, Mamede, Pinto, Susana, Mora Pardina, Jesus S., Povedano Panades, Mónica, Andersen, Peter M., Weber, Markus, Başak, Nazli A., Shaw, Christopher E., Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., Vourc’h, Patrick, Dobson, Richard J. B., Breen, Gerome, Al-Chalabi, Ammar, Jones, Ashley R., Iacoangeli, Alfredo, Adey, Brett N., Cooper-Knock, Johnathan, Al Khleifat, Ahmad, Fogh, Isabella, van Damme, Philip, Corcia, Philippe, Couratier, Philippe, Hardiman, Orla, McLaughlin, Russell, Gotkine, Marc, Drory, Vivian, Silani, Vincenzo, Ticozzi, Nicola, Veldink, Jan H., van den Berg, Leonard H., de Carvalho, Mamede, Pinto, Susana, Mora Pardina, Jesus S., Povedano Panades, Mónica, Andersen, Peter M., Weber, Markus, Başak, Nazli A., Shaw, Christopher E., Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., Vourc’h, Patrick, Dobson, Richard J. B., Breen, Gerome, Al-Chalabi, Ammar, Jones, Ashley R., and Iacoangeli, Alfredo

Abstract

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

Published
2023
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21. Clinical testing panels for ALS : global distribution, consistency, and challenges

Author

Dilliott, Allison A., Al Nasser, Ahmad, Elnagheeb, Marwa, Fifita, Jennifer, Henden, Lyndal, Keseler, Ingrid M., Lenz, Steven, Marriott, Heather, Mccann, Emily, Mesaros, Maysen, Opie-Martin, Sarah, Owens, Emma, Palus, Brooke, Ross, Justyne, Wang, Zhanjun, White, Hannah, Al-Chalabi, Ammar, Andersen, Peter M., Benatar, Michael, Blair, Ian, Cooper-Knock, Johnathan, Harrington, Elizabeth A., Heckmann, Jeannine, Landers, John, Moreno, Cristiane, Nel, Melissa, Rampersaud, Evadnie, Roggenbuck, Jennifer, Rouleau, Guy, Traynor, Bryan, Van Blitterswijk, Marka, Van Rheenen, Wouter, Veldink, Jan, Weishaupt, Jochen, Drury, Luke, Harms, Matthew B., Farhan, Sali M. K., Dilliott, Allison A., Al Nasser, Ahmad, Elnagheeb, Marwa, Fifita, Jennifer, Henden, Lyndal, Keseler, Ingrid M., Lenz, Steven, Marriott, Heather, Mccann, Emily, Mesaros, Maysen, Opie-Martin, Sarah, Owens, Emma, Palus, Brooke, Ross, Justyne, Wang, Zhanjun, White, Hannah, Al-Chalabi, Ammar, Andersen, Peter M., Benatar, Michael, Blair, Ian, Cooper-Knock, Johnathan, Harrington, Elizabeth A., Heckmann, Jeannine, Landers, John, Moreno, Cristiane, Nel, Melissa, Rampersaud, Evadnie, Roggenbuck, Jennifer, Rouleau, Guy, Traynor, Bryan, Van Blitterswijk, Marka, Van Rheenen, Wouter, Veldink, Jan, Weishaupt, Jochen, Drury, Luke, Harms, Matthew B., and Farhan, Sali M. K.

Abstract

Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS. Methods: We reviewed the National Institutes of Health (NIH) Genetic Testing Registry (GTR) and members of the ALS GCEP to source frequently used testing panels and compare the genes included on the tests. Results: 14 clinical panels specific to ALS from 14 laboratories covered 4 to 54 genes. All panels report on ANG, SOD1, TARDBP, and VAPB; 50% included or offered the option of including C9orf72 hexanucleotide repeat expansion (HRE) analysis. Of the 91 genes included in at least one of the panels, 40 (44.0%) were included on only a single panel. We could not find a direct link to ALS in the literature for 14 (15.4%) included genes. Conclusions: The variability across the surveyed clinical genetic panels is concerning due to the possibility of reduced diagnostic yields in clinical practice and risk of a missed diagnoses for patients. Our results highlight the necessity for consensus regarding the appropriateness of gene inclusions in clinical genetic ALS tests to improve its application for patients living with ALS and their families.

Published
2023
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22. Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

Author

Neurologen, Brain, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Adey, Brett N, Cooper-Knock, Johnathan, Al Khleifat, Ahmad, Fogh, Isabella, van Damme, Philip, Corcia, Philippe, Couratier, Philippe, Hardiman, Orla, McLaughlin, Russell, Gotkine, Marc, Drory, Vivian, Silani, Vincenzo, Ticozzi, Nicola, Veldink, Jan H, van den Berg, Leonard H, de Carvalho, Mamede, Pinto, Susana, Mora Pardina, Jesus S, Povedano Panades, Mónica, Andersen, Peter M, Weber, Markus, Başak, Nazli A, Shaw, Christopher E, Shaw, Pamela J, Morrison, Karen E, Landers, John E, Glass, Jonathan D, Vourc'h, Patrick, Dobson, Richard J B, Breen, Gerome, Al-Chalabi, Ammar, Jones, Ashley R, Iacoangeli, Alfredo, Neurologen, Brain, Genetic Risks, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Adey, Brett N, Cooper-Knock, Johnathan, Al Khleifat, Ahmad, Fogh, Isabella, van Damme, Philip, Corcia, Philippe, Couratier, Philippe, Hardiman, Orla, McLaughlin, Russell, Gotkine, Marc, Drory, Vivian, Silani, Vincenzo, Ticozzi, Nicola, Veldink, Jan H, van den Berg, Leonard H, de Carvalho, Mamede, Pinto, Susana, Mora Pardina, Jesus S, Povedano Panades, Mónica, Andersen, Peter M, Weber, Markus, Başak, Nazli A, Shaw, Christopher E, Shaw, Pamela J, Morrison, Karen E, Landers, John E, Glass, Jonathan D, Vourc'h, Patrick, Dobson, Richard J B, Breen, Gerome, Al-Chalabi, Ammar, Jones, Ashley R, and Iacoangeli, Alfredo

Published
2023

23. Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

Author

Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Adey, Brett N.; Cooper-Knock, Johnathan; Al Khleifat, Ahmad; Fogh, Isabella; van Damme, Philip; Corcia, Philippe; Couratier, Philippe; Hardiman, Orla; McLaughlin, Russell; Gotkine, Marc; Drory, Vivian; Silani, Vincenzo; Ticozzi, Nicola; Veldink, Jan H.; van den Berg, Leonard H.; de Carvalho, Mamede; Pinto, Susana; Mora Pardina, Jesus S.; Povedano Panades, Mónica; Andersen, Peter M.; Weber, Markus; Shaw, Christopher E.; Shaw, Pamela J.; Morrison, Karen E.; Landers, John E.; Glass, Jonathan D.; Vourc’h, Patrick; Dobson, Richard J. B.; Breen, Gerome; Al-Chalabi, Ammar; Jones, Ashley R.; Iacoangeli, Alfredo, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Adey, Brett N.; Cooper-Knock, Johnathan; Al Khleifat, Ahmad; Fogh, Isabella; van Damme, Philip; Corcia, Philippe; Couratier, Philippe; Hardiman, Orla; McLaughlin, Russell; Gotkine, Marc; Drory, Vivian; Silani, Vincenzo; Ticozzi, Nicola; Veldink, Jan H.; van den Berg, Leonard H.; de Carvalho, Mamede; Pinto, Susana; Mora Pardina, Jesus S.; Povedano Panades, Mónica; Andersen, Peter M.; Weber, Markus; Shaw, Christopher E.; Shaw, Pamela J.; Morrison, Karen E.; Landers, John E.; Glass, Jonathan D.; Vourc’h, Patrick; Dobson, Richard J. B.; Breen, Gerome; Al-Chalabi, Ammar; Jones, Ashley R.; Iacoangeli, Alfredo, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: we report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: these results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion., We would like to acknowledge funding from the following funders: UK Research and Innovation; Medical Research Council; South London and Maudsley NHS Foundation Trust; MND Scotland; Motor Neurone Disease Association; National Institute for Health Research; Spastic Paraplegia Foundation; Rosetrees Trust; Darby Rimmer MND Foundation. Funding for open access charge: UKRI. BA acknowledges funding from an NIHR pre-doctoral fellowship (NIHR301067). AI is funded by the Motor Neurone Disease Association and South London and Maudsley NHS Foundation Trust. JC-K is supported by a Wellcome Trust fellowship (216596/Z/19/Z). AAK is funded by ALS Association Milton Safenowitz Research Fellowship (grant number 22-PDF-609. DOI: 10.52546/pc.gr.150909.), The Motor Neurone Disease Association (MNDA) Fellowship (AAK/Oct21/975-799), The Darby Rimmer Foundation, and The NIHR Maudsley Biomedical Research Centre. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND: http://www.neurodegenerationresearch.eu/ [United Kingdom, Medical Research Council MR/L501529/1 to AA-C, principal investigator (PI) and MR/R024804/1 to AA-C, PI; Economic and Social Research Council ES/L008238/1 to AA-C (co-PI)] and through the Motor Neurone Disease Association. This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The work leading up to this publication was funded by the European Community’s Horizon 2020 Programme (H2020-PHC-2014-two-stage; grant 633413). We acknowledge use of the research computing facility at King’s College London, Rosalind ( https://rosalind.kcl.ac.uk ), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London and Maudsley and Guy’s and St.

Published
2023

26. Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

Author

Al Khleifat, Ahmad, primary, Iacoangeli, Alfredo, additional, Jones, Ashley R., additional, van Vugt, Joke J. F. A., additional, Moisse, Matthieu, additional, Shatunov, Aleksey, additional, Zwamborn, Ramona A. J., additional, van der Spek, Rick A. A., additional, Cooper-Knock, Johnathan, additional, Topp, Simon, additional, van Rheenen, Wouter, additional, Kenna, Brendan, additional, Van Eijk, Kristel R., additional, Kenna, Kevin, additional, Byrne, Ross, additional, López, Victoria, additional, Opie-Martin, Sarah, additional, Vural, Atay, additional, Campos, Yolanda, additional, Weber, Markus, additional, Smith, Bradley, additional, Fogh, Isabella, additional, Silani, Vincenzo, additional, Morrison, Karen E., additional, Dobson, Richard, additional, van Es, Michael A., additional, McLaughlin, Russell L., additional, Vourc’h, Patrick, additional, Chio, Adriano, additional, Corcia, Philippe, additional, de Carvalho, Mamede, additional, Gotkine, Marc, additional, Panades, Monica Povedano, additional, Mora, Jesus S., additional, Shaw, Pamela J., additional, Landers, John E., additional, Glass, Jonathan D., additional, Shaw, Christopher E., additional, Basak, Nazli, additional, Hardiman, Orla, additional, Robberecht, Wim, additional, Van Damme, Philip, additional, van den Berg, Leonard H., additional, Veldink, Jan H., additional, and Al-Chalabi, Ammar, additional

Published
2022
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28. Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

Author

Moll, Tobias, primary, Odon, Valerie, additional, Harvey, Calum, additional, Collins, Mark O, additional, Peden, Andrew, additional, Franklin, John, additional, Graves, Emily, additional, Marshall, Jack NG, additional, dos Santos Souza, Cleide, additional, Zhang, Sai, additional, Castelli, Lydia, additional, Hautbergue, Guillaume, additional, Azzouz, Mimoun, additional, Gordon, David, additional, Krogan, Nevan, additional, Ferraiuolo, Laura, additional, Snyder, Michael P, additional, Shaw, Pamela J, additional, Rehwinkel, Jan, additional, and Cooper-Knock, Johnathan, additional

Published
2022
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29. Clinical testing panels for ALS: global distribution, consistency, and challenges

Author

Dilliott, Allison A., primary, Al Nasser, Ahmad, additional, Elnageeb, Marwa, additional, Fifita, Jennifer, additional, Henden, Lyndal, additional, Keseler, Ingrid M., additional, Lenz, Steven, additional, Marriott, Heather, additional, McCann, Emily, additional, Mesaros, Maysen, additional, Opie-Martin, Sarah, additional, Owens, Emma, additional, Palus, Brooke, additional, Ross, Justyne, additional, Wang, Zhanjun, additional, White, Hannah, additional, Al-Chalabi, Ammar, additional, Andersen, Peter M., additional, Benatar, Michael, additional, Blair, Ian, additional, Cooper-Knock, Johnathan, additional, Drury, Luke, additional, Harrington, Elizabeth, additional, Heckmann, Jeannine, additional, Landers, John, additional, Moreno, Cristiane, additional, Nel, Melissa, additional, Rampersaud, Evadnie, additional, Roggenbuck, Jennifer, additional, Rouleau, Guy, additional, Traynor, Bryan, additional, van Blitterswijk, Marka, additional, van Rheenen, Wouter, additional, Veldink, Jan, additional, Weishaupt, Jochen, additional, Harms, Matthew B., additional, and Farhan, Sali M.K., additional

Published
2022
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31. Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity

Author

Zhang, Sai, primary, Cooper-Knock, Johnathan, additional, Weimer, Annika K., additional, Shi, Minyi, additional, Kozhaya, Lina, additional, Unutmaz, Derya, additional, Harvey, Calum, additional, Julian, Thomas H., additional, Furini, Simone, additional, Frullanti, Elisa, additional, Fava, Francesca, additional, Renieri, Alessandra, additional, Gao, Peng, additional, Shen, Xiaotao, additional, Timpanaro, Ilia Sarah, additional, Kenna, Kevin P., additional, Baillie, J. Kenneth, additional, Davis, Mark M., additional, Tsao, Philip S., additional, and Snyder, Michael P., additional

Published
2022
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32. AtypicalTDP‐43 protein expression in anALSpedigree carrying a p.Y374Xtruncation mutation inTARDBP

Author

Cooper‐Knock, Johnathan, primary, Julian, Thomas H., additional, Feneberg, Emily, additional, Highley, J. Robin, additional, Sidra, Maurice, additional, Turner, Martin R., additional, Talbot, Kevin, additional, Ansorge, Olaf, additional, Allen, Scott P., additional, Moll, Tobias, additional, Shelkovnikova, Tatyana, additional, Castelli, Lydia, additional, Hautbergue, Guillaume M., additional, Hewitt, Christopher, additional, Kirby, Janine, additional, Wharton, Stephen B., additional, Mead, Richard J., additional, and Shaw, Pamela J., additional

Published
2022
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34. Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Author

Brain, Neurogenetica, Neurologen, Zhang, Sai, Cooper-Knock, Johnathan, Weimer, Annika K, Shi, Minyi, Moll, Tobias, Marshall, Jack N G, Harvey, Calum, Nezhad, Helia Ghahremani, Franklin, John, Souza, Cleide Dos Santos, Ning, Ke, Wang, Cheng, Li, Jingjing, Dilliott, Allison A, Farhan, Sali, Elhaik, Eran, Pasniceanu, Iris, Livesey, Matthew R, Eitan, Chen, Hornstein, Eran, Kenna, Kevin P, Veldink, Jan H, Ferraiuolo, Laura, Shaw, Pamela J, Snyder, Michael P, Project MinE ALS Sequencing Consortium, Brain, Neurogenetica, Neurologen, Zhang, Sai, Cooper-Knock, Johnathan, Weimer, Annika K, Shi, Minyi, Moll, Tobias, Marshall, Jack N G, Harvey, Calum, Nezhad, Helia Ghahremani, Franklin, John, Souza, Cleide Dos Santos, Ning, Ke, Wang, Cheng, Li, Jingjing, Dilliott, Allison A, Farhan, Sali, Elhaik, Eran, Pasniceanu, Iris, Livesey, Matthew R, Eitan, Chen, Hornstein, Eran, Kenna, Kevin P, Veldink, Jan H, Ferraiuolo, Laura, Shaw, Pamela J, Snyder, Michael P, and Project MinE ALS Sequencing Consortium

Published
2022

35. Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

Author

Vural, Atay (ORCID 0000-0003-3222-874X & YÖK ID 182369); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Weber, Markus, Al Khleifat, Ahmad; Iacoangeli, Alfredo; Jones, Ashley R.; van Vugt, Joke J. F. A.; Moisse, Matthieu; Shatunov, Aleksey; Zwamborn, Ramona A. J.; van der Spek, Rick A. A.; Cooper-Knock, Johnathan; Topp, Simon; van Rheenen, Wouter; Kenna, Brendan; Van Eijk, Kristel R.; Kenna, Kevin; Byrne, Ross; Lopez, Victoria; Opie-Martin, Sarah; Campos, Yolanda; Smith, Bradley; Fogh, Isabella; Silani, Vincenzo; Morrison, Karen E.; Dobson, Richard; van Es, Michael A.; McLaughlin, Russell L.; Vourc'h, Patrick; Chio, Adriano; Corcia, Philippe; de Carvalho, Mamede; Gotkine, Marc; Panades, Monica Povedano; Mora, Jesus S.; Shaw, Pamela J.; Landers, John E.; Glass, Jonathan D.; Shaw, Christopher E.; Hardiman, Orla; Robberecht, Wim; Van Damme, Philip; van den Berg, Leonard H.; Veldink, Jan H.; Al-Chalabi, Ammar; the Project MinE Consortium, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Vural, Atay (ORCID 0000-0003-3222-874X & YÖK ID 182369); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Weber, Markus, Al Khleifat, Ahmad; Iacoangeli, Alfredo; Jones, Ashley R.; van Vugt, Joke J. F. A.; Moisse, Matthieu; Shatunov, Aleksey; Zwamborn, Ramona A. J.; van der Spek, Rick A. A.; Cooper-Knock, Johnathan; Topp, Simon; van Rheenen, Wouter; Kenna, Brendan; Van Eijk, Kristel R.; Kenna, Kevin; Byrne, Ross; Lopez, Victoria; Opie-Martin, Sarah; Campos, Yolanda; Smith, Bradley; Fogh, Isabella; Silani, Vincenzo; Morrison, Karen E.; Dobson, Richard; van Es, Michael A.; McLaughlin, Russell L.; Vourc'h, Patrick; Chio, Adriano; Corcia, Philippe; de Carvalho, Mamede; Gotkine, Marc; Panades, Monica Povedano; Mora, Jesus S.; Shaw, Pamela J.; Landers, John E.; Glass, Jonathan D.; Shaw, Christopher E.; Hardiman, Orla; Robberecht, Wim; Van Damme, Philip; van den Berg, Leonard H.; Veldink, Jan H.; Al-Chalabi, Ammar; the Project MinE Consortium, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Background: amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS. Methods: samples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression. Results: there were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10?12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10?7). Although there was no difference, European Community's Health Seventh Framework Program (FP7/2007-2013); European Union (EU); Horizon 2020; H2020-PHC2014-two-stage; European Research Council (ERC); Research and Innovation Programme; AAK was funded by ALS Association Milton Safenowitz Research Fellowship (grant number 22-PDF-609. doi: 10.52546/pc.gr.150909), The Motor Neurone Disease Association (MNDA) Fellowship (Al Khleifat/Oct21/975799), The Darby Rimmer Foundation, and The NIHRMaudsley Biomedical Research Centre. This project was also funded by the MND Association and the Wellcome Trust. This is an EU Joint Programme-Neurodegenerative Disease Research JPND) project. The project is supported through the following funding organizations under the aegis of JPND-www.jpnd.eu [United Kingdom, Medical Research Council (MR/L501529/1 and MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)]. AA-C was a NIHR Senior Investigator. CS and AA-C received salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London. The collaboration project was co-funded by the PPP Allowance made available by Health ~Holland, Top Sector Life Sciences and Health, to stimulate public-private partnerships. Project MinE Belgium was supported by a grant from IWT, the Belgian ALS Liga and a grant from Opening the Future Fund (KU Leuven). PVD holds a senior clinical investigatorship of FWO-Vlaanderen and was supported by E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga Belgie and the KU Leuven funds ""Een Hart voor ALS,"" ""Laeversfonds voor ALS Onderzoek,"" and the ""Valery Perrier Race against ALS Fund"". RM was supported by Science Foundation Ireland (17/CDA/4737). MinE USA was funded by the US ALS Association.

Published
2022

36. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Author

Neurogenetica, AIOS Psychiatrie, Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, Al Khleifat, Ahmad, Iacoangeli, Alfredo, van Vugt, Joke J F A, Bowles, Harry, Moisse, Matthieu, Zwamborn, Ramona A J, van der Spek, Rick A A, Shatunov, Aleksey, Cooper-Knock, Johnathan, Topp, Simon, Byrne, Ross, Gellera, Cinzia, López, Victoria, Jones, Ashley R, Opie-Martin, Sarah, Vural, Atay, Campos, Yolanda, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel R, Kenna, Kevin, Weber, Markus, Smith, Bradley, Fogh, Isabella, Silani, Vincenzo, Morrison, Karen E, Dobson, Richard, van Es, Michael A, McLaughlin, Russell L, Vourc'h, Patrick, Chio, Adriano, Corcia, Philippe, de Carvalho, Mamede, Gotkine, Marc, Panades, Monica P, Mora, Jesus S, Shaw, Pamela J, Landers, John E, Glass, Jonathan D, Shaw, Christopher E, Basak, Nazli, Hardiman, Orla, Robberecht, Wim, Van Damme, Philip, van den Berg, Leonard H, Veldink, Jan H, Al-Chalabi, Ammar, Neurogenetica, AIOS Psychiatrie, Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Genetic Risks, Neuromuscular Disorders, Al Khleifat, Ahmad, Iacoangeli, Alfredo, van Vugt, Joke J F A, Bowles, Harry, Moisse, Matthieu, Zwamborn, Ramona A J, van der Spek, Rick A A, Shatunov, Aleksey, Cooper-Knock, Johnathan, Topp, Simon, Byrne, Ross, Gellera, Cinzia, López, Victoria, Jones, Ashley R, Opie-Martin, Sarah, Vural, Atay, Campos, Yolanda, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel R, Kenna, Kevin, Weber, Markus, Smith, Bradley, Fogh, Isabella, Silani, Vincenzo, Morrison, Karen E, Dobson, Richard, van Es, Michael A, McLaughlin, Russell L, Vourc'h, Patrick, Chio, Adriano, Corcia, Philippe, de Carvalho, Mamede, Gotkine, Marc, Panades, Monica P, Mora, Jesus S, Shaw, Pamela J, Landers, John E, Glass, Jonathan D, Shaw, Christopher E, Basak, Nazli, Hardiman, Orla, Robberecht, Wim, Van Damme, Philip, van den Berg, Leonard H, Veldink, Jan H, and Al-Chalabi, Ammar

Published
2022

38. Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Author

Boddy, Sarah, primary, Islam, Mahjabin, additional, Moll, Tobias, additional, Kurz, Julian, additional, Burrows, David, additional, McGown, Alexander, additional, Bhargava, Anushka, additional, Julian, Thomas H, additional, Harvey, Calum, additional, Marshall, Jack NG, additional, Hall, Benjamin PC, additional, Allen, Scott P, additional, Kenna, Kevin P, additional, Sanderson, Eleanor, additional, Zhang, Sai, additional, Ramesh, Tennore, additional, Snyder, Michael P, additional, Shaw, Pamela J, additional, McDermott, Christopher, additional, and Cooper-Knock, Johnathan, additional

Published
2022
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39. Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Author

Zhang, Sai, primary, Cooper-Knock, Johnathan, additional, Weimer, Annika K., additional, Shi, Minyi, additional, Moll, Tobias, additional, Marshall, Jack N.G., additional, Harvey, Calum, additional, Nezhad, Helia Ghahremani, additional, Franklin, John, additional, Souza, Cleide dos Santos, additional, Ning, Ke, additional, Wang, Cheng, additional, Li, Jingjing, additional, Dilliott, Allison A., additional, Farhan, Sali, additional, Elhaik, Eran, additional, Pasniceanu, Iris, additional, Livesey, Matthew R., additional, Eitan, Chen, additional, Hornstein, Eran, additional, Kenna, Kevin P., additional, Veldink, Jan H., additional, Ferraiuolo, Laura, additional, Shaw, Pamela J., additional, Snyder, Michael P., additional, Blair, Ian, additional, Wray, Naomi R., additional, Kiernan, Matthew, additional, Mitne Neto, Miguel, additional, Chio, Adriano, additional, Cauchi, Ruben, additional, Robberecht, Wim, additional, van Damme, Philip, additional, Corcia, Philippe, additional, Couratier, Philippe, additional, Hardiman, Orla, additional, McLaughin, Russell, additional, Gotkine, Marc, additional, Drory, Vivian, additional, Ticozzi, Nicola, additional, Silani, Vincenzo, additional, van den Berg, Leonard H., additional, de Carvalho, Mamede, additional, Mora Pardina, Jesus S., additional, Povedano, Monica, additional, Andersen, Peter, additional, Weber, Markus, additional, Başak, Nazli A., additional, Al-Chalabi, Ammar, additional, Shaw, Chris, additional, Morrison, Karen E., additional, Landers, John E., additional, and Glass, Jonathan D., additional

Published
2022
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40. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Author

Rheenen, Wouter van, Spek, Rick A. A. van der, Bakker, Mark K., Vugt, Joke J. F. A. van, Hop, Paul J., Zwamborn, Ramona A. J., Klein, Niek de, Westra, Harm Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Needham, Merrilee, Ceroni, Mauro, Simoncini, Costanza, Gagliardi, Stella, Corrado, Lucia, Garton, Fleur C., Mazzini, Letizia, Westeneng, Henk Jan, Ross, Jay P., Valluzzi, Francesco, Aguggia, Marco, Raggi, Flavia, Rini, Augusto, Traynor, Bryan J., Singleton, Andrew B., Ngo, Shyuan T., Corcia, Philippe, Olsen, Catherine M., Hofman, Albert, Van Eijk, Kristel R., Pasterkamp, R. Jeroen, Tittmann, Lukas, Iacoangeli, Alfredo, Mitne Neto, Miguel, Sproviero, Daisy, Cauchi, Ruben J., Ophoff, Roel A., Wiedau Pazos, Martina, Lomen-Hoerth, Catherine, Deerlin, Vivianna M. van, Nicholson, Garth A., Brylev, Lev, Whiteman, David C., Grosskreutz, Julian, Fan, Dongsheng, Couratier, Philippe, Roediger, Annekathrin, Gaur, Nayana, D’alfonso, Sandra, Uitterlinden, André G., Pamphlett, Roger, Fominykh, Vera, Byrne, Ross P., Lieb, Wolfgang, Iazzolino, Barbara, Dekker, Annelot M., Slap Consortium, Demeshonok, Vera, Millecamps, Stéphanie, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Franke, Andre, Mcrae, Allan F., Rowe, Dominic B., Peotta, Laura, Cooper-Knock, Johnathan, Glavač, Damjan, Doherty, Mark, Rietschel, Marcella, Stević, Zorica, Drory, Vivian, Meininger, Vincent, Zarrelli, Michele, Povedano, Monica, Gaunt, Tom R., Steyn, Frederik J., Williams, Kelly L., Smith, Bradley N., Cugnasco, Paolo, Papurello, Diego Maria, Nozzoli, Cecilia, Sorarù, Gianni, Mather, Karen A., Ripke, Stephan, Nöthen, Markus M., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, Carvalho, Mamede de, Gromicho, Marta, Pinto, Susana, Marco, Giovanni de, Al Khleifat, Ahmad, Eberle, Michael A., Braun, Alice, Gusmaroli, Graziano, Siciliano, Gabriele, Petri, Susanne, Breen, Gerome, Weber, Markus, Rouleau, Guy A., Rojas García, Ricardo, Silani, Vincenzo, Amouyel, Philippe, Ghiglione, Paolo, Davey Smith, George, Curtis, Charles J., Shatunov, Aleksey, Mill, Jonathan, Mclaughlin, Russell L., Filosto, Massimiliano, Comi, Cristoforo, Gerfo, Annalisa lo, Ferlini, Alessandra, Riva, Nilo, Mora Pardina, Jesus S., Chiveri, Luca, Hardiman, Orla, Torrieri, Maria Claudia, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Padovani, Alessandro, Chandran, Siddharthan, Al Chalabi, Ammar, Assialioui, Abdelilah, Labate, Carmelo, Damme, Philip van, Ticozzi, Nicola, Palumbo, Francesca, Inghilleri, Maurizio, Chiò, Adriano, Pal, Suvankar, Lunetta, Christian, Jörk, Alexander, Cichon, Sven, Kraft, Julia, Morrison, Karen E., Ruiz, Luigi, Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Dion, Patrick A., Calvo, Andrea, Kooyman, Maarten, Başak, Nazli, Gerardi, Francesca, Simone, Isabella L., Kooi, Anneke J. van der, Ratti, Antonia, Ferrandi, Delfina, Fogh, Isabella, Ludolph, Albert C., Moglia, Cristina, Brunetti, Maura, Diamanti, Luca, Barthel, Tabea, Blair, Ian P., Es, Michael A. van, Gallone, Salvatore, Canosa, Antonio, Guerra, Vito, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Ferrarese, Carlo, Nefussy, Beatrice, Theele, Erik, Rinaldi, Fabrizio, Weishaupt, Jochen H., Kiernan, Matthew C., Barberis, Marco, Osmanovic, Alma, Baloh, Robert H., Nordin, Angelica, Lerner, Yossef, Vito, Nicoletta di, Zabari, Michal, Zoccolella, Stefano, Heverin, Mark, Gotkine, Marc, Guaita, Maria Cristina, Brenner, David, Freischmidt, Axel, Sbaiz, Luca, Benyamin, Beben, Glass, Jonathan D., Landers, John E., Tazelaar, Gijs H. P., Rota, Eugenia, Bensimon, Gilbert, Ilse, Benjamin, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Gentile, Salvatore, Moisse, Matthieu, Topp, Simon, Henderson, Robert D., Rademakers, Rosa, Perrone, Patrizia, Stubendorff, Beatrice, Brown, Robert H., Restuadi, Restuadi, Tremolizzo, Lucio, Mundi, Ciro, Berg, Leonard H. van den, Passarella, Bruno, Delodovici, Maria Luisa, Furlong, Sarah, Bono, Giorgio, Manera, Umberto, Vasta, Rosario, Bombaci, Alessandro, Meineri, Piero, Mauro, Alessandro, Hannon, Eilis, Casale, Federico, Leone, Maurizio, Shaw, Christopher E., Fuda, Giuseppe, Salamone, Paolina, Mathers, Susan, Baird, Denis, Launaro, Nicola, Marchi, Fabiola de, Veldink, Jan H., Gellera, Cinzia, Salachas, François, Witte, Otto W., Andersen, Peter M., Bertolotto, Antonio, Gionco, Maurizio, Leotta, Daniela, Odddenino, Enrico, Slalom Consortium, Tamma, Filippo, Dotta, Michele, Lauria, Giuseppe, Steinbach, Robert, Imperiale, Daniele, Geda, Claudio, Dolzhenko, Egor, Cavallo, Roberto, Pignatta, Pietro, Groen, Ewout J. N., Cotelli, Maria Sofia, Mattei, Marco de, Calabrese, Gianluigi, Sapio, Alessia di, Giardini, Guido, Hübner, Christian A., Corti, Stefania, Bell, Shaughn, Comi, Giancarlo, Mccombe, Pamela A., Tiloca, Cinzia, Parals Consortium, Gawor, Klara, Peverelli, Silvia, Taroni, Franco, Pensato, Viviana, Castellotti, Barbara, Graff, Caroline, Comi, Giacomo P., Cereda, Cristina, Bo, Roberto del, Boero, Giovanni, Slagen Consortium, Vourc’h, Patrick, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), van Rheenen, Wouter, van der Spek, Rick AA, Bakker, Mark K, van Vugt, Joke JFA, Benyamin, Beben, Veldink, Jan H, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, SLAP Consortium, van Rheenen, W, van der Spek, R, Bakker, M, van Vugt, J, Hop, P, Zwamborn, R, de Klein, N, Westra, H, Bakker, O, Deelen, P, Shireby, G, Hannon, E, Moisse, M, Baird, D, Restuadi, R, Dolzhenko, E, Dekker, A, Gawor, K, Westeneng, H, Tazelaar, G, van Eijk, K, Kooyman, M, Byrne, R, Doherty, M, Heverin, M, Al Khleifat, A, Iacoangeli, A, Shatunov, A, Ticozzi, N, Cooper-Knock, J, Smith, B, Gromicho, M, Chandran, S, Pal, S, Morrison, K, Shaw, P, Hardy, J, Orrell, R, Sendtner, M, Meyer, T, Basak, N, van der Kooi, A, Ratti, A, Fogh, I, Gellera, C, Lauria, G, Corti, S, Cereda, C, Sproviero, D, D'Alfonso, S, Soraru, G, Siciliano, G, Filosto, M, Padovani, A, Chio, A, Calvo, A, Moglia, C, Brunetti, M, Canosa, A, Grassano, M, Beghi, E, Pupillo, E, Logroscino, G, Nefussy, B, Osmanovic, A, Nordin, A, Lerner, Y, Zabari, M, Gotkine, M, Baloh, R, Bell, S, Vourc'H, P, Corcia, P, Couratier, P, Millecamps, S, Meininger, V, Salachas, F, Mora Pardina, J, Assialioui, A, Rojas-Garcia, R, Dion, P, Ross, J, Ludolph, A, Weishaupt, J, Brenner, D, Freischmidt, A, Bensimon, G, Brice, A, Durr, A, Payan, C, Saker-Delye, S, Wood, N, Topp, S, Rademakers, R, Tittmann, L, Lieb, W, Franke, A, Ripke, S, Braun, A, Kraft, J, Whiteman, D, Olsen, C, Uitterlinden, A, Hofman, A, Rietschel, M, Cichon, S, Nothen, M, Amouyel, P, Traynor, B, Singleton, A, Mitne Neto, M, Cauchi, R, Ophoff, R, Wiedau-Pazos, M, Lomen-Hoerth, C, van Deerlin, V, Grosskreutz, J, Roediger, A, Gaur, N, Jork, A, Barthel, T, Theele, E, Ilse, B, Stubendorff, B, Witte, O, Steinbach, R, Hubner, C, Graff, C, Brylev, L, Fominykh, V, Demeshonok, V, Ataulina, A, Rogelj, B, Koritnik, B, Zidar, J, Ravnik-Glavac, M, Glavac, D, Stevic, Z, Drory, V, Povedano, M, Blair, I, Kiernan, M, Benyamin, B, Henderson, R, Furlong, S, Mathers, S, Mccombe, P, Needham, M, Ngo, S, Nicholson, G, Pamphlett, R, Rowe, D, Steyn, F, Williams, K, Mather, K, Sachdev, P, Henders, A, Wallace, L, de Carvalho, M, Pinto, S, Petri, S, Weber, M, Rouleau, G, Silani, V, Curtis, C, Breen, G, Glass, J, Brown, R, Landers, J, Shaw, C, Andersen, P, Groen, E, van Es, M, Pasterkamp, R, Fan, D, Garton, F, Mcrae, A, Davey Smith, G, Gaunt, T, Eberle, M, Mill, J, Mclaughlin, R, Hardiman, O, Kenna, K, Wray, N, Tsai, E, Runz, H, Franke, L, Al-Chalabi, A, Van Damme, P, van den Berg, L, Veldink, J, Ferrarese, C, Neurology, ANS - Neuroinfection & -inflammation, APH - Methodology, APH - Quality of Care, EURO-NMD, Internal Medicine, Epidemiology, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), van Rheenen, W., Van der Spek, R.A.A., Bakker, M.K., van Vugt, J.J.F.A., Hop, P.J., Zwamborn, R.A.J., de Klein, N., Westra, H.J., Bakker, O.B., Deelen, P., Shireby, G., Hannon, E., Moisse, M., Baird, D., Restuadi, R., Dolzhenko, E., Dekker, A.M., Gawor, K., Westeneng, H.J., Tazelaar, G.H.P., van Eijk, K.R., Kooyman, M., Byrne, R.P., Doherty, M., Heverin, M., Al Khleifat, A., Iacoangeli, A., Shatunov, A., Ticozzi, N., Cooper-Knock, J., Smith, B.N., Gromicho, M., Chandran, S., Pal, S., Morrison, K.E., Shaw, P.J., Hardy, J., Orrell, R.W., Sendtner, M., Meyer, T., van der Kooi, A.J., Ratti, A., Fogh, I., Gellera, C., Lauria, G., Corti, S., Cereda, C., Sproviero, D., D'Alfonso, S., Sorarù, G., Siciliano, G., Filosto, M., Padovani, A., Chiò, A., Calvo, A., Moglia, C., Brunetti, M., Canosa, A., Grassano, M., Beghi, E., Pupillo, E., Logroscino, G., Nefussy, B., Osmanovic, A., Nordin, A., Lerner, Y., Zabari, M., Gotkine, M., Baloh, R.H., Bell, S., Vourc'h, P., Corcia, P., Couratier, P., Millecamps, S., Meininger, V., Salachas, F., Mora Pardina, J.S., Assialioui, A., Rojas-García, R., Dion, P.A., Ross, J.P., Ludolph, A.C., Weishaupt, J.H., Brenner, D., Freischmidt, A., Bensimon, G., Brice, A., Durr, A., Payan, C.A.M., Saker-Delye, S., Wood, N.W., Topp, S., Rademakers, R., Tittmann, L., Lieb, W., Franke, A., Ripke, S., Kraft, J.,Whiteman, David C., Olsen, Catherine M., Uitterlinden, A.G., Hofman, A., Rietschel, M., Cichon, S., Nothen, M.M., Amouyel, P., Comi, G., Riva, N., Lunetta, C., Gerardi, F., Cotelli, M.S., Rinaldi, F., Chiveri, L., Guaita, M.C., Perrone, P., Ceroni, M., Diamanti, L., Ferrarese, C., Tremolizzo, L., Delodovici, M.L., Bono, G., Manera, U., Vasta, R., Bombaci, A., Casale, F., Fuda, G., Salamone, P., Iazzolino, B., Peotta, L., Cugnasco, P., De Marco, G., Torrieri, M.C., Palumbo, F., Gallone, S., Barberis, M., Sbaiz, L., Gentile, S., Mauro, A., Mazzini, L., De Marchi, F., Corrado, L., Bertolotto, A., Gionco, M., Leotta, D., Odddenino, E., Imperiale, D., Cavallo, R., Pignatta, P., De Mattei, M., Geda, C., Papurello, D.M., Gusmaroli, G., Comi, C., Labate, C., Ruiz, L., Ferrandi, D., Rota, E., Aguggia, M., Di Vito, N., Meineri, P., Ghiglione, P., Launaro, N., Dotta, M., Di Sapio, A., Giardini, G., Tiloca, C., Peverelli, S., Taroni, F., Pensato, V., Castellotti, B., Comi, G.P., Del Bo, R., Gagliardi, S., Raggi, F., Simoncini, C., Lo Gerfo, A., Inghilleri, M., Ferlini, A., Simone, I.L., Passarella, B., Guerra, V., Zoccolella, S., Nozzoli, C., Mundi, C., Leone, M., Zarrelli, M., Tamma, F., Valluzzi, F., Calabrese, G., Boero, G., Rini, A., Traynor, B.J., Singleton, A.B., Neto, M.M., Cauchi, R.J., Ophoff, R.A., Wiedau-Pazos, M., Lomen-Hoerth, C., van Deerlin, V.M., Grosskreutz, J., Roediger, A., Gaur, N., Jork, A., Barthel, T., Theele, E., Ilse, B., Stubendorff, B., Witte, O.W., Steinbach, R., Hubner, C.A., Graff, C., Brylev, L., Fominykh, V., Demeshonok, V., Ataulina, A., Rogelj, B., Koritnik, B., Zidar, J., Ravnik-Glavac, M., Glavac, D., Stevic, Z., Drory, V., Povedano, M., Blair, I.P., Kiernan, M.C., Benyamin, B., Henderson, R.D., Furlong, S., Mathers, S., McCombe, P.A, Needham, M., Ngo, S.T., Nicholson, G.A., Pamphlett, R., Rowe, D.B., Steyn, F.J., Williams, K.L., Mather, K.A., Sachdev, P.S., Henders, A.K., Wallace, L., de Carvalho, M., Pinto, S., Petri, S., Weber, M., Rouleau, G.A., Silani, V., Curtis, C.J., Breen, G., Glass, J.D., Brown, R.H., Landers, J.E., Shaw, C.E., Andersen, P.M., Groen, E.J.N, van Es, M.A., Pasterkamp, R.J., Fan, D.S., Garton, F.C., McRae, A.F., Smith, G.D., Gaunt, T.R., Eberle, M.A., Mill, J., McLaughlin, R.L., Hardiman, O., Kenna, K.P., Wray, N.R., Tsai, E.L., Runz, H., Franke, L., Al-Chalabi, A., Van Damme, P., van den Berg, L.H., Veldink, J.H., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Subjects
Male, Genetics and heredity, amyotrophic lateral sclerosis, Neurologi, Glutamine, Medizin, Genome-wide association study, Disease, SUSCEPTIBILITY, Genome-wide association studies, DISEASE, Genètica mèdica, 0302 clinical medicine, neurodegenerative disease, genome-wide association study, ALS, gene, autophagy, Risk Factors, amyotrophic lateral sclerosi, RNA-Seq, Amyotrophic lateral sclerosis, disease-modifying therapies, blood [Cholesterol], Genetics, Genetics & Heredity, Neurons, 0303 health sciences, Medical genetics, Neurodegenerative diseases, Genome-wide association, Mendelian randomization, Frontotemporal dementia, Hexanucleotide repeat, Mutant SOD1, Metaanalysis, ALS, Susceptibility, Identification, Brain, Amyotrophic Lateral Sclerosis, Cholesterol, Disease Progression, Female, Humans, Mendelian Randomization Analysis, Microsatellite Repeats, Neurodegenerative Diseases, Quantitative Trait Loci, Genome-Wide Association Study, Mutation, MUTANT SOD1, genetics [Amyotrophic Lateral Sclerosis], medicine.anatomical_structure, Neurology, risk factor, metabolism [Neurons], MENDELIAN RANDOMIZATION, nerve cell, Life Sciences & Biomedicine, quantitative trait locu, Biology, 03 medical and health sciences, Amyotrophic lateral sclerosis -- Diagnosis, blood, ddc:570, medicine, degenerative disease, Motor neuron disease, human, Genomes, GENOME-WIDE ASSOCIATION, gene, Gene, metabolism [Glutamine], METAANALYSIS, 030304 developmental biology, Mendelian randomization analysi, Science & Technology, HEXANUCLEOTIDE REPEAT, meta analysi, IDENTIFICATION, metabolism [Amyotrophic Lateral Sclerosis], FRONTOTEMPORAL DEMENTIA, medicine.disease, metabolism [Brain], genetics [Neurodegenerative Diseases], Expression quantitative trait loci, disease exacerbation, Neuron, gemone, genetic, Vesicle-mediated transport, metabolism, Nervous system -- Degeneration, Esclerosi lateral amiotròfica, 030217 neurology & neurosurgery
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., Dutch Research Council (NWO); VENI Scheme Grant; VIDI Grant; Prinses Beatrix Spierfonds; Neuromuscular Fellowship Grant; Medical Research Council (MRC); Clinical Infrastructure Award; Epidemiology Unit; Integrative Epidemiology Unit; Canadian Institutes of Health Research; IWT; National Institute on Aging; National Health and Medical Research Council (NHMRC); Enabling Grant; NHMRC/Australian Research Council Strategic Award; NHMRC; NHMRC Centre of Research Excellence Grant; National Health and Medical Research Council of Australia (NHMRC) Research Fellowship; United Kingdom, Medical Research Council; Economic and Social Research Council; European Union (EU); Horizon 2020; European Community's Health Seventh Framework Programme; EuroMOTOR; European Research Council (ERC); Research and Innovation Programme; EScORIAL; ALS Foundation Netherlands; Alzheimer’s Society PhD Studentship; ARSla Funding; Biogen; University of Bristol; Motor Neurone Disease Association (MNDA); NIHR Maudsley Biomedical Research Centre; Dutch Ministry of Education, Culture, and Science; Netherlands Organization for Scientific Research (NWO; BRAINSCAPES); Gravitation Program; ALS Liga België; National Lottery of Belgium; KU Leuven Opening the Future Fund; KU Leuven Funds, “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund”; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Liga België; “Live now” Charity Foundation; Moscow ALS palliative Care Service; Canadian Institutes of Health; Research Australia; Ice Bucket Challenge Grant; NIH Intramural Research Programs; FightMND Mid-Career Fellowship; NIHR Senior Investigator; Sheffield NIHR Biomedical Research Centre; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre; Maudsley NHS Foundation Trust; King’s College London; NIHR Senior Investigator Award; Netherlands Organization for Health Research and Development; Vici Scheme; Netherlands Organization for Health Research and Development STRENGTH Project; PPP Allowance

Published
2021

44. Atypical TDP‐43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP.

Author

Cooper‐Knock, Johnathan, Julian, Thomas H., Feneberg, Emily, Highley, J. Robin, Sidra, Maurice, Turner, Martin R., Talbot, Kevin, Ansorge, Olaf, Allen, Scott P., Moll, Tobias, Shelkovnikova, Tatyana, Castelli, Lydia, Hautbergue, Guillaume M., Hewitt, Christopher, Kirby, Janine, Wharton, Stephen B., Mead, Richard J., and Shaw, Pamela J.

Subjects
*AMYOTROPHIC lateral sclerosis, *PROTEIN expression, *MOTOR cortex, *NONSENSE mutation, *MOTOR neurons, *FIBROBLASTS, *GENEALOGY, *MASS spectrometry
Abstract

We describe an autosomal dominant, multi‐generational, amyotrophic lateral sclerosis (ALS) pedigree in which disease co‐segregates with a heterozygous p.Y374X nonsense mutation within TDP‐43. Mislocalization of TDP‐43 and formation of insoluble TDP‐43‐positive neuronal cytoplasmic inclusions is the hallmark pathology in >95% of ALS patients. Neuropathological examination of the single case for which CNS tissue was available indicated typical TDP‐43 pathology within lower motor neurons, but classical TDP‐43‐positive inclusions were absent from motor cortex. The mutated allele is transcribed and translated in patient fibroblasts and motor cortex tissue, but overall TDP‐43 protein expression is reduced compared to wild‐type controls. Despite absence of TDP‐43‐positive inclusions we confirmed deficient TDP‐43 splicing function within motor cortex tissue. Furthermore, urea fractionation and mass spectrometry of motor cortex tissue carrying the mutation revealed atypical TDP‐43 protein species but not typical C‐terminal fragments. We conclude that the p.Y374X mutation underpins a monogenic, fully penetrant form of ALS. Reduced expression of TDP‐43 combined with atypical TDP‐43 protein species and absent C‐terminal fragments extends the molecular phenotypes associated with TDP‐43 mutations and with ALS more broadly. Future work will need to include the findings from this pedigree in dissecting the mechanisms of TDP‐43‐mediated toxicity. [ABSTRACT FROM AUTHOR]

Published
2023
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45. Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication.

Author

Moll, Tobias, Odon, Valerie, Harvey, Calum, Collins, Mark O., Peden, Andrew, Franklin, John, Graves, Emily, Marshall, Jack N. G., dos Santos Souza, Cleide, Sai Zhang, Castelli, Lydia, Hautbergue, Guillaume, Azzouz, Mimoun, Gordon, David, Krogan, Nevan, Ferraiuolo, Laura, Snyder, Michael P., Shaw, Pamela J., Rehwinkel, Jan, and Cooper-Knock, Johnathan

Published
2023
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46. A review of Mendelian randomization in amyotrophic lateral sclerosis

Author

Julian, Thomas H, primary, Boddy, Sarah, additional, Islam, Mahjabin, additional, Kurz, Julian, additional, Whittaker, Katherine J, additional, Moll, Tobias, additional, Harvey, Calum, additional, Zhang, Sai, additional, Snyder, Michael P, additional, McDermott, Christopher, additional, Cooper-Knock, Johnathan, additional, and Shaw, Pamela J, additional

Published
2021
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47. A review of Mendelian randomization in amyotrophic lateral sclerosis.

Author

Julian, Thomas H, Boddy, Sarah, Islam, Mahjabin, Kurz, Julian, Whittaker, Katherine J, Moll, Tobias, Harvey, Calum, Zhang, Sai, Snyder, Michael P, McDermott, Christopher, Cooper-Knock, Johnathan, and Shaw, Pamela J

Subjects
RESEARCH evaluation, TYPE 2 diabetes, AMYOTROPHIC lateral sclerosis, RESEARCH funding, NEURODEGENERATION, LIPIDS
Abstract

Amyotrophic lateral sclerosis is a relatively common and rapidly progressive neurodegenerative disease that, in the majority of cases, is thought to be determined by a complex gene-environment interaction. Exponential growth in the number of performed genome-wide association studies combined with the advent of Mendelian randomization is opening significant new opportunities to identify environmental exposures that increase or decrease the risk of amyotrophic lateral sclerosis. Each of these discoveries has the potential to shape new therapeutic interventions. However, to do so, rigorous methodological standards must be applied in the performance of Mendelian randomization. We have reviewed Mendelian randomization studies performed in amyotrophic lateral sclerosis to date. We identified 20 Mendelian randomization studies, including evaluation of physical exercise, adiposity, cognitive performance, immune function, blood lipids, sleep behaviours, educational attainment, alcohol consumption, smoking and type 2 diabetes mellitus. We have evaluated each study using gold standard methodology supported by the Mendelian randomization literature and the STROBE-Mendelian randomization checklist. Where discrepancies exist between Mendelian randomization studies, we suggest the underlying reasons. A number of studies conclude that there is a causal link between blood lipids and risk of amyotrophic lateral sclerosis; replication across different datasets and even different populations adds confidence. For other putative risk factors, such as smoking and immune function, Mendelian randomization studies have provided cause for doubt. We highlight the use of positive control analyses in choosing exposure single nucleotide polymorphisms (SNPs) to make up the Mendelian randomization instrument, use of SNP clumping to avoid false positive results due to SNPs in linkage and the importance of multiple testing correction. We discuss the implications of survival bias for study of late age of onset diseases such as amyotrophic lateral sclerosis and make recommendations to mitigate this potentially important confounder. For Mendelian randomization to be useful to the amyotrophic lateral sclerosis field, high methodological standards must be applied to ensure reproducibility. Mendelian randomization is already an impactful tool, but poor-quality studies will lead to incorrect interpretations by a field that includes non-statisticians, wasted resources and missed opportunities. [ABSTRACT FROM AUTHOR]

Published
2022
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48. Simultaneous ALS and SCA2 associated with an intermediate-length ATXN2 CAG-repeat expansion.

Author

Ghahremani Nezhad, Helia, Franklin, John P., Alix, James J. P., Moll, Tobias, Pattrick, Michael, Cooper-Knock, Johnathan, Shanmugarajah, Priya, Beauchamp, Nick J., Hadjivissiliou, Marios, Paling, David, Mcdermott, Christopher, Shaw, Pamela J., and Jenkins, Thomas M.

Subjects
SPINOCEREBELLAR ataxia, FRONTOTEMPORAL lobar degeneration, AMYOTROPHIC lateral sclerosis, MEDICAL personnel, SYMPTOMS, AGE of onset
Abstract

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) share a common molecular basis: both are associated with CAG-repeat expansion of ATXN2 and TDP-43-positive neuronal cytoplasmic inclusions. To date, the two disorders are viewed as clinically distinct with ALS resulting from 30-33 CAG-repeats and SCA2 from >34 CAG-repeats. We describe a 67-year old with a 32 CAG-repeat expansion of ATXN2 who presented with simultaneous symptoms of ALS and SCA2. Our case demonstrates that the clinical dichotomy between SCA2 and ATXN2-ALS is false. We suggest instead that CAG-repeat expansion length determines the timing of SCA2 clinical symptoms relative to onset of ALS; consistent with this age of onset of SCA2 but not ATXN2-ALS, is dependent upon expansion length. Review of the literature and our local cohort provides evidence for occurrence of ALS in late stage SCA2, which may be under-recognised by clinicians who think of the two diseases as distinct. [ABSTRACT FROM AUTHOR]

Published
2021
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50. Profiling of somatic, population and phenotypic heterogeneity in genetic causes of ALS/MND

Author

Haque, Shaila, Kirby, Janine, and Cooper-Knock, Johnathan

Abstract

Amyotrophic Lateral Sclerosis (ALS) or Motor Neurone Disease (MND) is a rapidly progressive and universally fatal neurological disorder. While some genetic causes have been discovered, much remains unknown, especially in different populations. Brachial monomelic amyotrophy (MMA) is a rare condition that mimics MND, but with a better prognosis. The genetic basis of MMA is currently unknown. In this study, DNA samples from the motor cortex of ALS cases were genotyped using whole genome sequencing (WGS) to compare results with those previously found in peripheral blood to screen for the presence of somatic mutations. Targeted sequencing of ALS genes in 28 Bangladeshi MND patients, including 11 MMA patients, was performed and compared with results from 8 UK MMA patients to establish if there was genetic link between the two diseases. Two SOD1 and a FUS mutation were found in the motor cortex samples but had previously been found in peripheral blood, not supporting the hypothesis of somatic heterogeneity. Screening of Bangladesh samples revealed 99 variants in 32 ALS risk genes, including pathogenic SOD1 mutations in 3 patients. Forty-three variants of conflicting interpretations (n=17), uncertain significance (n=12), risk factor (n=1) and unknown (n=13) were found in MMA patients, highlighting a shared genetic basis of MMA and MND. This is supported by the presence of TDP-43 pathology in UK MMA patient samples. The study discovered the genetic basis of MND in Bangladesh was overlapping but distinct compared to the UK, with no C9ORF72 mutations found in the Bangladeshi MND cases. Further work is needed to validate the variants currently designated as variants of uncertain significance in both MMA and MND patients.

Published
2023

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