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Genome-wide analyses identify KIF5A as a novel ALS gene

Genome-wide analyses identify KIF5A as a novel ALS gene
Genome-wide analyses identify KIF5A as a novel ALS gene
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
0896-6273
1268-1283.e6
Nicolas, Aude
35090169-8879-464b-a7b0-f13414c7aa64
Kenna, Kevin
c3e6403d-0870-4cd4-9bad-a3c3140312a8
Renton, Alan E.
3f9f3e66-abc5-4bb5-800a-8f7a292c4c9c
Morrison, Karen
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
ITALSGEN Consortium
Genomic Translation for ALS Care (GTAC) Consortium
ALS Sequencing Consortium
NYGC ALS Consortium
Answer ALS Foundation
Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium
SLAGEN Consortium
French ALS Consortium
Project MinE ALS Sequencing Consortium
et al.
Nicolas, Aude
35090169-8879-464b-a7b0-f13414c7aa64
Kenna, Kevin
c3e6403d-0870-4cd4-9bad-a3c3140312a8
Renton, Alan E.
3f9f3e66-abc5-4bb5-800a-8f7a292c4c9c
Morrison, Karen
f00890f0-2fde-4dbd-a73b-7422e1b0ede8

Nicolas, Aude, Kenna, Kevin and Renton, Alan E. , ITALSGEN Consortium, Genomic Translation for ALS Care (GTAC) Consortium, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Foundation, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consortium and et al. (2018) Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron, 97 (6), 1268-1283.e6. (doi:10.1016/j.neuron.2018.02.027).

Record type: Article

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

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KIF5A_ALS_02_07_18 - Accepted Manuscript
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Accepted/In Press date: 26 February 2018
e-pub ahead of print date: 21 March 2018
Published date: 21 March 2018

Identifiers

Local EPrints ID: 420668
URI: http://eprints.soton.ac.uk/id/eprint/420668
ISSN: 0896-6273
PURE UUID: 67956de1-7f4d-45d8-8b80-3d84027c3362
ORCID for Karen Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 11 May 2018 16:30
Last modified: 07 Oct 2020 04:44

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Contributors

Author: Aude Nicolas
Author: Kevin Kenna
Author: Alan E. Renton
Author: Karen Morrison ORCID iD
Corporate Author: ITALSGEN Consortium
Corporate Author: Genomic Translation for ALS Care (GTAC) Consortium
Corporate Author: ALS Sequencing Consortium
Corporate Author: NYGC ALS Consortium
Corporate Author: Answer ALS Foundation
Corporate Author: Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium
Corporate Author: SLAGEN Consortium
Corporate Author: French ALS Consortium
Corporate Author: Project MinE ALS Sequencing Consortium
Corporate Author: et al.

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