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 Calbiac, François Muratet, Sylvie Dirrig-Grosch, Stéphane Dieterle, Nick Bakel, Kathrin Müller, Kirsten Sieverding, Jochen Weishaupt, Peter Munch Andersen, Markus Weber, Christoph Neuwirth, Markus Margelisch, Andreas Sommacal, Kristel R. Eijk, Jan H. Veldink, Géraldine Lautrette, Philippe Couratier, Agnès Camuzat, Isabelle Ber, Maurizio Grassano, Adriano Chio, Tobias Boeckers, Albert C. Ludolph, Francesco Roselli, Deniz Yilmazer-Hanke, Stéphanie Millecamps, Edor Kabashi, Erik Storkebaum, Chantal Sellier and Luc Dupuis ()
Additional contact information
Salim Megat: Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine
Natalia Mora: 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: Ulm University
Najwa Ouali Alami: 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 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 Bakel: Radboud University
Kathrin Müller: German Center for Neurodegenerative Diseases (DZNE) Ulm
Kirsten Sieverding: German Center for Neurodegenerative Diseases (DZNE) Ulm
Jochen Weishaupt: University Medicine Mannheim, Heidelberg University
Peter Munch Andersen: 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. Eijk: University Medical Center Utrecht Brain Center, Utrecht University
Jan H. Veldink: University Medical Center Utrecht Brain Center, Utrecht University
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 Ber: Sorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière
Maurizio Grassano: University of Turin
Adriano Chio: University of Turin
Tobias Boeckers: Ulm University
Albert C. Ludolph: German Center for Neurodegenerative Diseases (DZNE) Ulm
Francesco Roselli: German Center for Neurodegenerative Diseases (DZNE) Ulm
Deniz Yilmazer-Hanke: 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: 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

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-022-35724-1

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