Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

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

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Pages (from-to)1268-1283.e6
JournalNeuron
Volume97
Issue number6
DOIs
StatePublished - Mar 21 2018

Fingerprint

Kinesin
Genome
Mutation
Genes
Genome-Wide Association Study
Hereditary Spastic Paraplegia
Exome
Phenotype
Neurodegenerative Diseases
Tooth
Survival

Keywords

  • ALS
  • axonal transport
  • cargo
  • GWAS
  • KIF5A
  • WES
  • WGS

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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, ... Project MinE ALS Sequencing Consortium (2018). Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97(6), 1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. / 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.

In: Neuron, Vol. 97, No. 6, 21.03.2018, p. 1268-1283.e6.

Research output: Contribution to journalArticle

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 2018, 'Genome-wide Analyses Identify KIF5A as a Novel ALS Gene', Neuron, vol. 97, no. 6, pp. 1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027
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 et al. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron. 2018 Mar 21;97(6):1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027
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. / Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. In: Neuron. 2018 ; Vol. 97, No. 6. pp. 1268-1283.e6.
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AU - Salvi, Fabrizio

AU - Bartolomei, Ilaria

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AU - Tranquilli, Stefania

AU - Cuccu, Stefania

AU - Corongiu, Daniela

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AU - Ostrow, Lyle

AU - Rothstein, Jeffrey D

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KW - axonal transport

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KW - KIF5A

KW - WES

KW - WGS

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