Integrative genetic analysis illuminates ALS heritability and identifies risk genes.

Publication

Integrative genetic analysis illuminates ALS heritability and identifies risk genes.

Journal Paper/Review - Jan 20, 2023

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

Citation

Megat S, Mora N, Sanogo J, Roman O, Catanese A, Alami N, Freischmidt A, Mingaj X, De Calbiac H, Muratet F, Dirrig-Grosch S, Dieterle S, Van Bakel N, Müller K, Sieverding K, Weishaupt J, Andersen P, Weber M, Neuwirth C, Margelisch M, Sommacal A, van Eijk K, Veldink J, PROJECT MINE ALS SEQUENCING CONSORTIUM, Lautrette G, Couratier P, Camuzat A, Le Ber I, Grassano M, Chio A, Boeckers T, Ludolph A, Roselli F, Yilmazer-Hanke D, Millecamps S, Kabashi E, Storkebaum E, Sellier C, Dupuis L. Integrative genetic analysis illuminates ALS heritability and identifies risk genes. Nat Commun 2023; 14:342.

Type

Journal Paper/Review (English)

Journal

Nat Commun 2023; 14

Publication Date

Jan 20, 2023

Issn Electronic

2041-1723

Pages

342

Brief description/objective

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; 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.