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 journalArticlepeer-review

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
Pages (from-to)1268-1283.e6
JournalNeuron
Volume97
Issue number6
DOIs
StatePublished - 21 Mar 2018
Externally publishedYes

Funding

FundersFunder number
Fondazione Vialli e Mauro onlus
Ulla-Carin Lindquists stiftelse för ALS-forskning
Epidermolysis Bullosa Medical Research Foundation
Alzheimer's Society
Merck
Centers for Disease Control and Prevention
Angel Fund
Knut och Alice Wallenbergs Stiftelse
Università degli Studi di Torino
Flanders Innovation & Enterpreneurship
Engineering Research Centers
ALS Therapy Alliance
MND Association of England, Wales and Northern Ireland
Compagnia di San Paolo
Västerbotten Läns Landsting
Italian Health Ministry
Neuroförbundet Association
Voyager Therapeutics
UK Dementia Research Institute
NIHR UCLH
European Community’s Health Seventh Framework Programme
Motor Neurone Disease Association
National Institutes of Health
Guy's and St Thomas' Charity
European Commission
Wellcome Trust
Microsoft Research
Science Foundation Ireland
Bertil Hållsten Foundation
MRC Neuromuscular Centre , UK National Institute for Health Research Biomedical Research Unit
Medical Research Foundation
E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
Motor Neurone Disease Research Institute of Australia
Hjärnfonden
Consortium canadien en neurodégénérescence associée au vieillissement
Helsingin ja Uudenmaan Sairaanhoitopiiri
H2020 European Research Council
NS061867
Health Research Board
Suna and Inan Kirac Foundation
Regione Piemonte
Heaton-Ellis Trust
Torsten Söderbergs Stiftelse
ALS Finding a Cure
Vetenskapsrådet
ALS liga België
Sigrid Juséliuksen Säätiö
Agentschap voor Innovatie door Wetenschap en Technologie
Noreen Murray Foundation
National Heart, Lung, and Blood InstituteK25HL121295
National Heart, Lung, and Blood Institute
Alzheimer’s Research UKMRF-060-0003-RG-SMITH
Alzheimer’s Research UK
NIHR Biomedical Research Centre for Translational NeuroscienceIS-BRC-1215-20017
National Institute of Neurological Disorders and StrokeU54NS092091, R01NS073873, R56NS061867, ZIANS003154, R35NS097261, U54NS091046, P01NS084974
National Institute of Neurological Disorders and Stroke
Medical Research CouncilMC_PC_17115, MR/L021803/1, MR/L016397/1, G0600974, MR/M008606/1, G0900688, MR/R024804/1, MR/L501529/1, G0500289, MR/K01014X/1
Medical Research Council
Amyotrophic Lateral Sclerosis Association17-LGCA-331, 16-LGCA-308, 15-LGCA-235, 15-LGCA-234, 16-LGCA-310
Amyotrophic Lateral Sclerosis Association
National Institute of Environmental Health SciencesK23ES027221
National Institute of Environmental Health Sciences
United States National Institute on AgingN01-AG-5-0002, 263 MD 821336, N.1-AG-1-2111, 263 MD 9164
Seventh Framework Programme259867, 340429
Seventh Framework Programme
U.S. Department of Veterans AffairsI01BX002466
U.S. Department of Veterans Affairs
National Institute on AgingZ01AG000949, P50AG005146, P30AG013846, ZIAAG000933, N01-AG-5-0002, P01AG017586, 263 MD 821336, N.1-AG-1-2111, N.1-AG-1-1
National Institute on Aging
National Health and Medical Research Council1107644, 1095215
National Health and Medical Research Council
Academy of Finland294817
Academy of Finland
Tow FoundationICS110.1/RF97.71, 90072272
Tow Foundation
National Institute on Disability and Rehabilitation ResearchNF-SI-0512-10082
National Institute on Disability and Rehabilitation Research
Muscular Dystrophy AssociationR01NS073873
Muscular Dystrophy Association
National Institute on Minority Health and Health DisparitiesR01MD009164
National Institute on Minority Health and Health Disparities
Ministero della SaluteGR-2011-02347820 - IRisALS
Ministero della Salute

    Keywords

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

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