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  • Marriott, HeatherDepartment 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 (författare)

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

  • Artikel/kapitelEngelska2024

Förlag, utgivningsår, omfång ...

  • 2024
  • John Wiley & Sons,2024
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:umu-226966
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-226966URI
  • https://doi.org/10.1002/acn3.52083DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

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Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Spargo, Thomas P.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 (författare)
  • Al Khleifat, AhmadDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (författare)
  • Andersen, Peter M.,1962-Umeå universitet,Institutionen för klinisk vetenskap(Swepub:umu)pean0001 (författare)
  • Başak, Nazli A.Translational Medicine Research Center, NDAL, School of Medicine, Koc University, Istanbul, Turkey (författare)
  • Cooper-Knock, JohnathanSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom (författare)
  • Corcia, PhilippeUMR 1253, Université de Tours, Inserm, Tours, France; Centre de référence sur la SLA, CHU de Tours, Tours, France (författare)
  • Couratier, PhilippeCentre de référence sur la SLA, CHRU de Limoges, Limoges, France; UMR 1094, Université de Limoges, Inserm, Limoges, France (författare)
  • de Carvalho, MamedeInstituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal (författare)
  • Drory, VivianDepartment of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel (författare)
  • Gotkine, MarcFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah Medical Center, Jerusalem, Israel (författare)
  • Landers, John E.Department of Neurology, University of Massachusetts Medical School, MA, Worcester, United States (författare)
  • McLaughlin, RussellComplex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland (författare)
  • Pardina, Jesús S. MoraALS Unit, Hospital San Rafael, Madrid, Spain (författare)
  • Morrison, Karen E.School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom (författare)
  • Pinto, SusanaInstituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal (författare)
  • Shaw, Christopher E.Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (författare)
  • Shaw, Pamela J.Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom (författare)
  • Silani, VincenzoDepartment 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 (författare)
  • Ticozzi, NicolaDepartment 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 (författare)
  • van Damme, PhilipExperimental 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 (författare)
  • van den Berg, Leonard H.Department of Neurology, UMC Utrecht Brain Center, University Medical Center, Utrecht, Netherlands (författare)
  • Vourc'h, PatrickUMR 1253, Université de Tours, Inserm, Tours, France; Service de Biochimie et Biologie molécularie, CHU de Tours, Tours, France (författare)
  • Weber, MarkusNeuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland (författare)
  • Veldink, Jan H.Department of Neurology, UMC Utrecht Brain Center, University Medical Center, Utrecht, Netherlands (författare)
  • Dobson, Richard J.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 (författare)
  • Schwab, PatrickGlaxoSmithKline, Artificial Intelligence and Machine Learning, London, United Kingdom (författare)
  • Al-Chalabi, AmmarDepartment 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 (författare)
  • Iacoangeli, AlfredoDepartment 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 (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 KingdomDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Annals of Clinical and Translational Neurology: John Wiley & Sons2328-9503

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