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Integrative genetic analysis illuminates ALS heritability and identifies risk genes

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)...

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Main Authors: Megat, Salim (Author) , Mora, Natalia (Author) , Sanogo, Jason (Author) , Roman, Olga (Author) , Catanese, Alberto (Author) , Alami, Najwa Ouali (Author) , Freischmidt, Axel (Author) , Mingaj, Xhuljana (Author) , De Calbiac, Hortense (Author) , Muratet, François (Author) , Dirrig-Grosch, Sylvie (Author) , Dieterle, Stéphane (Author) , Van Bakel, Nick (Author) , Müller, Kathrin (Author) , Sieverding, Kirsten (Author) , Weishaupt, Jochen H. (Author) , Andersen, Peter Munch (Author) , Weber, Markus (Author) , Neuwirth, Christoph (Author) , Margelisch, Markus (Author) , Sommacal, Andreas (Author) , Van Eijk, Kristel R. (Author) , Veldink, Jan H. (Author) , Lautrette, Géraldine (Author) , Couratier, Philippe (Author) , Camuzat, Agnès (Author) , Le Ber, Isabelle (Author) , Grassano, Maurizio (Author) , Chio, Adriano (Author) , Böckers, Tobias M. (Author) , Ludolph, Albert C. (Author) , Roselli, Francesco (Author) , Yilmazer-Hanke, Deniz (Author) , Millecamps, Stéphanie (Author) , Kabashi, Edor (Author) , Storkebaum, Erik (Author) , Sellier, Chantal (Author) , Dupuis, Luc (Author)
Format: Article (Journal)
Language:English
Published: 2023
In: Nature Communications
Year: 2023, Volume: 14, Pages: 1-18
ISSN:2041-1723
DOI:10.1038/s41467-022-35724-1
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-022-35724-1
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-022-35724-1
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Author Notes: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
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Summary: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.
Item Description:Veröffentlicht: 20. Januar 2023
Gesehen am 16.08.2023
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-022-35724-1

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