Integrative genetic analysis illuminates ALS heritability and identifies risk genes
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 stud...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-022-35724-1 |
| _version_ | 1797397877814722560 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Salim Megat |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T01:16:35Z |
| format | Article |
| id | doaj.art-6c41a4f4e8fe4f95afcbf96cee484c70 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T01:16:35Z |
| publishDate | 2023-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-6c41a4f4e8fe4f95afcbf96cee484c702023-12-10T12:24:56ZengNature PortfolioNature Communications2041-17232023-01-0114111810.1038/s41467-022-35724-1Integrative genetic analysis illuminates ALS heritability and identifies risk genesSalim Megat0Natalia Mora1Jason Sanogo2Olga Roman3Alberto Catanese4Najwa Ouali Alami5Axel Freischmidt6Xhuljana Mingaj7Hortense De Calbiac8François Muratet9Sylvie Dirrig-Grosch10Stéphane Dieterle11Nick Van Bakel12Kathrin Müller13Kirsten Sieverding14Jochen Weishaupt15Peter Munch Andersen16Markus Weber17Christoph Neuwirth18Markus Margelisch19Andreas Sommacal20Kristel R. Van Eijk21Jan H. Veldink22Project Mine Als Sequencing ConsortiumGéraldine Lautrette23Philippe Couratier24Agnès Camuzat25Isabelle Le Ber26Maurizio Grassano27Adriano Chio28Tobias Boeckers29Albert C. Ludolph30Francesco Roselli31Deniz Yilmazer-Hanke32Stéphanie Millecamps33Edor Kabashi34Erik Storkebaum35Chantal Sellier36Luc Dupuis37Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en BiomédecineDepartment of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud UniversityUniversité de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en BiomédecineUniversité de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en BiomédecineInstitute of Anatomy and Cell Biology, Ulm UniversityClinical Neuroanatomy, Department of Neurology, Ulm UniversityGerman Center for Neurodegenerative Diseases (DZNE) UlmLaboratory of Translational Research for Neurological Disorders, Imagine Institute, Université de Paris, INSERM UMR 1163Laboratory of Translational Research for Neurological Disorders, Imagine Institute, Université de Paris, INSERM UMR 1163Sorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS, APHP, Hôpital de la Pitié SalpêtrièreUniversité de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en BiomédecineUniversité de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en BiomédecineDepartment of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud UniversityGerman Center for Neurodegenerative Diseases (DZNE) UlmGerman Center for Neurodegenerative Diseases (DZNE) UlmDivision for Neurodegenerative Diseases, Neurology Department, University Medicine Mannheim, Heidelberg UniversityDepartment of Clinical Science, Neurosciences, Umea UniversityNeuromuscular Disease Unit/ALS Clinic, Kantonsspital St. GallenNeuromuscular Disease Unit/ALS Clinic, Kantonsspital St. GallenInstitute for Pathology, Kanstonsspital St. GallenInstitute for Pathology, Kanstonsspital St. GallenDepartment of Neurology, University Medical Center Utrecht Brain Center, Utrecht UniversityDepartment of Neurology, University Medical Center Utrecht Brain Center, Utrecht UniversityService de Neurologie, Centre de Référence SLA et autres maladies du neurone moteur, CHU Dupuytren 1Service de Neurologie, Centre de Référence SLA et autres maladies du neurone moteur, CHU Dupuytren 1Sorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS, APHP, Hôpital de la Pitié SalpêtrièreSorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS, APHP, Hôpital de la Pitié SalpêtrièreALS Center “Rita Levi Montalcini” Department of Neuroscience, University of TurinALS Center “Rita Levi Montalcini” Department of Neuroscience, University of TurinInstitute of Anatomy and Cell Biology, Ulm UniversityGerman Center for Neurodegenerative Diseases (DZNE) UlmGerman Center for Neurodegenerative Diseases (DZNE) UlmClinical Neuroanatomy, Department of Neurology, Ulm UniversitySorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS, APHP, Hôpital de la Pitié SalpêtrièreLaboratory of Translational Research for Neurological Disorders, Imagine Institute, Université de Paris, INSERM UMR 1163Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud UniversityUniversité de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en BiomédecineUniversité de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en BiomédecineAbstract 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.https://doi.org/10.1038/s41467-022-35724-1 |
| spellingShingle | 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 Integrative genetic analysis illuminates ALS heritability and identifies risk genes Nature Communications |
| title | Integrative genetic analysis illuminates ALS heritability and identifies risk genes |
| title_full | Integrative genetic analysis illuminates ALS heritability and identifies risk genes |
| title_fullStr | Integrative genetic analysis illuminates ALS heritability and identifies risk genes |
| title_full_unstemmed | Integrative genetic analysis illuminates ALS heritability and identifies risk genes |
| title_short | Integrative genetic analysis illuminates ALS heritability and identifies risk genes |
| title_sort | integrative genetic analysis illuminates als heritability and identifies risk genes |
| url | https://doi.org/10.1038/s41467-022-35724-1 |
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