Journal Article

Integrative genetic analysis illuminates ALS heritability and identifies risk genes

Veldink, Jan H., Ludolph, Albert C., Kabashi, Edor, Weishaupt, Jochen, Roselli, Francesco, Le Ber, Isabelle, Roman, Olga, Grassano, Maurizio, Storkebaum, Erik, Müller, Kathrin, Megat, Salim, Lautrette, Géraldine, Dupuis, Luc, Freischmidt, Axel, Camuzat, Agnès, Millecamps, Stéphanie, Boeckers, Tobias, De Calbiac, Hortense, Couratier, Philippe, Margelisch, Markus, Dieterle, Stéphane, Mingaj, Xhuljana, Weber, Markus, Dirrig-Grosch, Sylvie, Sommacal, Andreas, Sanogo, Jason, Muratet, François, Catanese, Alberto, Alami, Najwa Ouali, Yilmazer-Hanke, Deniz, Sieverding, Kirsten, Neuwirth, Christoph, Van Bakel, Nick, Andersen, Peter Munch, Sellier, Chantal, Chio, Adriano, Mora, Natalia, Van Eijk, Kristel R.

2023

Overview

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. ALS is somewhat heritable, but the genetic basis is not completely understood. Here, the authors identify alterations in splicing in neurons associated with amyotrophic lateral sclerosis and uncover several associated genetic loci, with a potential link to nuclear pore defects.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/23 / 38/43 / 38/89 / 631/208/480 / 631/378/1689/1285 / 64/116 / 64/24 / 64/60 / 692/308/2056 / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Animals / Binding sites / Biochemistry, Molecular Biology / Defects / Dementia disorders / Disease Models, Animal / Frameshift mutation / Frontotemporal dementia / Frontotemporal Dementia - genetics / Genetic analysis / Genomics / Heritability / Human health and pathology / Humanities and Social Sciences / Humans / Life Sciences / multidisciplinary / Mutation / Neurobiology / Neurons / Neurons - metabolism / Neurons and Cognition / Nuclear pores / Proteins / RNA-binding protein / RNA-Binding Protein FUS - genetics / RNA-Binding Protein FUS - metabolism / Science / Science (multidisciplinary) / Splicing / Transcriptomes / Zebrafish / Zebrafish - metabolism