Nature Communications (Jan 2023)
Integrative genetic analysis illuminates ALS heritability and identifies risk genes
- Salim Megat,
- Natalia Mora,
- Jason Sanogo,
- Olga Roman,
- Alberto Catanese,
- Najwa Ouali Alami,
- Axel Freischmidt,
- Xhuljana Mingaj,
- Hortense De Calbiac,
- François Muratet,
- Sylvie Dirrig-Grosch,
- Stéphane Dieterle,
- Nick Van Bakel,
- Kathrin Müller,
- Kirsten Sieverding,
- Jochen Weishaupt,
- Peter Munch Andersen,
- Markus Weber,
- Christoph Neuwirth,
- Markus Margelisch,
- Andreas Sommacal,
- Kristel R. Van Eijk,
- Jan H. Veldink,
- Project Mine Als Sequencing Consortium,
- Géraldine Lautrette,
- Philippe Couratier,
- Agnès Camuzat,
- Isabelle Le Ber,
- Maurizio Grassano,
- Adriano Chio,
- Tobias Boeckers,
- Albert C. Ludolph,
- Francesco Roselli,
- Deniz Yilmazer-Hanke,
- Stéphanie Millecamps,
- Edor Kabashi,
- Erik Storkebaum,
- Chantal Sellier,
- Luc Dupuis
Affiliations
- Salim Megat
- Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine
- Natalia Mora
- Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University
- Jason Sanogo
- Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine
- Olga Roman
- Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine
- Alberto Catanese
- Institute of Anatomy and Cell Biology, Ulm University
- Najwa Ouali Alami
- Clinical Neuroanatomy, Department of Neurology, Ulm University
- Axel Freischmidt
- German Center for Neurodegenerative Diseases (DZNE) Ulm
- Xhuljana Mingaj
- Laboratory of Translational Research for Neurological Disorders, Imagine Institute, Université de Paris, INSERM UMR 1163
- Hortense De Calbiac
- Laboratory of Translational Research for Neurological Disorders, Imagine Institute, Université de Paris, INSERM UMR 1163
- François Muratet
- Sorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière
- Sylvie Dirrig-Grosch
- Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine
- Stéphane Dieterle
- Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine
- Nick Van Bakel
- Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University
- Kathrin Müller
- German Center for Neurodegenerative Diseases (DZNE) Ulm
- Kirsten Sieverding
- German Center for Neurodegenerative Diseases (DZNE) Ulm
- Jochen Weishaupt
- Division for Neurodegenerative Diseases, Neurology Department, University Medicine Mannheim, Heidelberg University
- Peter Munch Andersen
- Department of Clinical Science, Neurosciences, Umea University
- Markus Weber
- Neuromuscular Disease Unit/ALS Clinic, Kantonsspital St. Gallen
- Christoph Neuwirth
- Neuromuscular Disease Unit/ALS Clinic, Kantonsspital St. Gallen
- Markus Margelisch
- Institute for Pathology, Kanstonsspital St. Gallen
- Andreas Sommacal
- Institute for Pathology, Kanstonsspital St. Gallen
- Kristel R. Van Eijk
- Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University
- Jan H. Veldink
- Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University
- Project Mine Als Sequencing Consortium
- Géraldine Lautrette
- Service de Neurologie, Centre de Référence SLA et autres maladies du neurone moteur, CHU Dupuytren 1
- Philippe Couratier
- Service de Neurologie, Centre de Référence SLA et autres maladies du neurone moteur, CHU Dupuytren 1
- Agnès Camuzat
- Sorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière
- Isabelle Le Ber
- Sorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière
- Maurizio Grassano
- ALS Center “Rita Levi Montalcini” Department of Neuroscience, University of Turin
- Adriano Chio
- ALS Center “Rita Levi Montalcini” Department of Neuroscience, University of Turin
- Tobias Boeckers
- Institute of Anatomy and Cell Biology, Ulm University
- Albert C. Ludolph
- German Center for Neurodegenerative Diseases (DZNE) Ulm
- Francesco Roselli
- German Center for Neurodegenerative Diseases (DZNE) Ulm
- Deniz Yilmazer-Hanke
- Clinical Neuroanatomy, Department of Neurology, Ulm University
- Stéphanie Millecamps
- Sorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière
- Edor Kabashi
- Laboratory of Translational Research for Neurological Disorders, Imagine Institute, Université de Paris, INSERM UMR 1163
- Erik Storkebaum
- Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University
- Chantal Sellier
- Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine
- Luc Dupuis
- Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine
- DOI
- https://doi.org/10.1038/s41467-022-35724-1
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 18
Abstract
Abstract Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10−03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.
