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

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

Marriott, Heather (författare): Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom

Spargo, Thomas P. (författare): Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom

Al Khleifat, Ahmad (författare): Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom

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Andersen, Peter M., 1962- (författare): Umeå universitet,Institutionen för klinisk vetenskap

Başak, Nazli A. (författare): Translational Medicine Research Center, NDAL, School of Medicine, Koc University, Istanbul, Turkey

Cooper-Knock, Johnathan (författare): Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom

Corcia, Philippe (författare): UMR 1253, Université de Tours, Inserm, Tours, France; Centre de référence sur la SLA, CHU de Tours, Tours, France

Couratier, Philippe (författare): Centre de référence sur la SLA, CHRU de Limoges, Limoges, France; UMR 1094, Université de Limoges, Inserm, Limoges, France

de Carvalho, Mamede (författare): Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

Drory, Vivian (författare): Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Gotkine, Marc (författare): Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah Medical Center, Jerusalem, Israel

Landers, John E. (författare): Department of Neurology, University of Massachusetts Medical School, MA, Worcester, United States

McLaughlin, Russell (författare): Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland

Pardina, Jesús S. Mora (författare): ALS Unit, Hospital San Rafael, Madrid, Spain

Morrison, Karen E. (författare): School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom

Pinto, Susana (författare): Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

Shaw, Christopher E. (författare): Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom

Shaw, Pamela J. (författare): Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom

Silani, Vincenzo (författare): Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy

Ticozzi, Nicola (författare): Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy

van Damme, Philip (författare): Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium; VIB, Center for Brain and Disease Research, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium

van den Berg, Leonard H. (författare): Department of Neurology, UMC Utrecht Brain Center, University Medical Center, Utrecht, Netherlands

Vourc'h, Patrick (författare): UMR 1253, Université de Tours, Inserm, Tours, France; Service de Biochimie et Biologie molécularie, CHU de Tours, Tours, France

Weber, Markus (författare): Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland

Veldink, Jan H. (författare): Department of Neurology, UMC Utrecht Brain Center, University Medical Center, Utrecht, Netherlands

Dobson, Richard J. (författare): Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Institute of Health Informatics, University College London, London, UK; NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust, London, UK

Schwab, Patrick (författare): GlaxoSmithKline, Artificial Intelligence and Machine Learning, London, United Kingdom

Al-Chalabi, Ammar (författare): Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; King's College Hospital, London, United Kingdom

Iacoangeli, Alfredo (författare): Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom

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2024
2024
Engelska.
Ingår i: Annals of Clinical and Translational Neurology. - : John Wiley & Sons. - 2328-9503.

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://umu.diva-por... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; visa färre...

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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.

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

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