Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
Name
nihms950505.pdf
Description
Accepted version
Size
1.07 MB
Format
Adobe PDF
Checksum (MD5)
be7a38c80f4227543a375eac4f9a3cf3
Date Issued
2018
Journal
Neuron
Publisher
Elsevier BV
Version
Author's final manuscript
Abstract
© 2018 Elsevier Inc. 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. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.NEURON.2018.02.027
