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 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; 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

doi:10.1038/s41467-022-35724-1

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 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, 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^*,

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	342
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-35724-1
Publication status	Published - Dec 2023

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s41467-022-35724-1Final published version, 7.05 MBLicence: CC BY

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Megat, S., Mora, N., Sanogo, J., Roman, O., Catanese, A., Alami, N. O., 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. M., Weber, M., Neuwirth, C. (2023). Integrative genetic analysis illuminates ALS heritability and identifies risk genes. Nature Communications, 14(1), Article 342. https://doi.org/10.1038/s41467-022-35724-1

@article{b05af16e394e4f4c984de2b0a235f752,

title = "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 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.",

author = "Salim Megat and Natalia Mora and Jason Sanogo and Olga Roman and Alberto Catanese and Alami, \{Najwa Ouali\} and Axel Freischmidt and Xhuljana Mingaj and \{De Calbiac\}, Hortense and Fran{\c c}ois Muratet and Sylvie Dirrig-Grosch and St{\'e}phane Dieterle and \{Van Bakel\}, Nick and Kathrin M{\"u}ller and Kirsten Sieverding and Jochen Weishaupt and Andersen, \{Peter Munch\} and Markus Weber and Christoph Neuwirth and Markus Margelisch and Andreas Sommacal and \{Van Eijk\}, \{Kristel R.\} and Veldink, \{Jan H.\} and G{\'e}raldine Lautrette and Philippe Couratier and Agn{\`e}s Camuzat and \{Le Ber\}, Isabelle and Maurizio Grassano and Adriano Chio and Tobias Boeckers and Ludolph, \{Albert C.\} and Francesco Roselli and Deniz Yilmazer-Hanke and St{\'e}phanie Millecamps and Edor Kabashi and Erik Storkebaum and Chantal Sellier and Luc Dupuis",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-022-35724-1",

language = "English",

volume = "14",

journal = "Nature Communications",

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Megat, S, Mora, N, Sanogo, J, Roman, O, Catanese, A, Alami, NO, Freischmidt, A, Mingaj, X, De Calbiac, H, Muratet, F, Dirrig-Grosch, S, Dieterle, S, Van Bakel, N, Müller, K, Sieverding, K, Weishaupt, J, Andersen, PM, Weber, M, Neuwirth, C, Margelisch, M, Sommacal, A, Van Eijk, KR, Veldink, JH, Lautrette, G, Couratier, P, Camuzat, A, Le Ber, I, Grassano, M, Chio, A, Boeckers, T, Ludolph, AC, Roselli, F, Yilmazer-Hanke, D, Millecamps, S, Kabashi, E, Storkebaum, E, Sellier, C, Dupuis, L 2023, 'Integrative genetic analysis illuminates ALS heritability and identifies risk genes', Nature Communications, vol. 14, no. 1, 342. https://doi.org/10.1038/s41467-022-35724-1

TY - JOUR

T1 - Integrative genetic analysis illuminates ALS heritability and identifies risk genes

AU - Megat, Salim

AU - Mora, Natalia

AU - Sanogo, Jason

AU - Roman, Olga

AU - Catanese, Alberto

AU - Alami, Najwa Ouali

AU - Freischmidt, Axel

AU - Mingaj, Xhuljana

AU - De Calbiac, Hortense

AU - Muratet, François

AU - Dirrig-Grosch, Sylvie

AU - Dieterle, Stéphane

AU - Van Bakel, Nick

AU - Müller, Kathrin

AU - Sieverding, Kirsten

AU - Weishaupt, Jochen

AU - Andersen, Peter Munch

AU - Weber, Markus

AU - Neuwirth, Christoph

AU - Margelisch, Markus

AU - Sommacal, Andreas

AU - Van Eijk, Kristel R.

AU - Veldink, Jan H.

AU - Lautrette, Géraldine

AU - Couratier, Philippe

AU - Camuzat, Agnès

AU - Le Ber, Isabelle

AU - Grassano, Maurizio

AU - Chio, Adriano

AU - Boeckers, Tobias

AU - Ludolph, Albert C.

AU - Roselli, Francesco

AU - Yilmazer-Hanke, Deniz

AU - Millecamps, Stéphanie

AU - Kabashi, Edor

AU - Storkebaum, Erik

AU - Sellier, Chantal

AU - Dupuis, Luc

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85146753491

U2 - 10.1038/s41467-022-35724-1

DO - 10.1038/s41467-022-35724-1

M3 - Article

C2 - 36670122

AN - SCOPUS:85146753491

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 342

ER -

Integrative genetic analysis illuminates ALS heritability and identifies risk genes

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Author Correction: Integrative genetic analysis illuminates ALS heritability and identifies risk genes (Nature Communications, (2023), 14, 1, (342), 10.1038/s41467-022-35724-1)

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