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

183 Scopus citations

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

Bibliographical note

Funding Information:
The ALS Association (ALSA) provided funding support to Project MinE (15-LGCA-235), the NYGC ALS Consortium (15-LGCA-234), the CReATe Consortium (17-LGCA-331), the GTAC Consortium (16-LGCA-310), the Target ALS Human Postmortem Tissue Core (16-LGCA-308), and NeuroLINCS, an NIH-funded collaborative effort. P.V.D. is a senior investigator of FWO-Vlaanderen. Project MinE Belgium has been supported by ALS liga België Flanders Innovation & Enterpreneurship (IWT grant Project MinE), the Belgian National Lottery, and a grant from Opening the Future Fund (KU Leuven). W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders and ERC (grant agreement no. 340429). Additional funding support includes NINDS R35 NS097261 (R.R.) and P01NS084974 (R.R. and K.B.B.). A.N.B. thanks the Suna and Inan Kirac Foundation, Istanbul, TR for its generous support of the Neurodegeneration Research Laboratory throughout this study. Funding for this work was provided by the Heaton-Ellis Trust, the Middlemass Family, Motor Neurone Disease Association, Medical Research Council, Medical Research Foundation, the Psychiatry Research Trust of the Institute of Psychiatry, Guy's and St Thomas’ Charity, the Wellcome Trust, and the Noreen Murray Foundation (C.E.S.). This work was also supported by the UK Dementia Research Institute, which is funded by the Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK (C.E.S.). The salary for B.N.S. was funded by the Medical Research Foundation (MRF) (MRF-060-0003-RG-SMITH). P.C.S. was supported through the auspices of Dr. H. Robert Horvitz (Massachusetts Institute of Technology), an Investigator of the Howard Hughes Institute. Support for this work came from the Department of Veterans Affairs and NIH (P30AG13846) to N.W.K. I.P.B. is supported by the Motor Neurone Disease Research Institute of Australia and the National Health and Medical Research Council of Australia (1107644 and 1095215). P.F. is supported by an MRC/MNDA LEWF and by NIHR UCLH BRC. Research support from NIH/NIEHS (K23ES027221), the ALS Association, Target ALS, and Cytokinetics was provided to S.A.G. M. Cudkowicz was awarded funding from ALS Finding a Cure. N.T., C. Tiloca, C.G., V.S., and J.E.L. received research support from AriSLA – Fondazione Italiana di Ricerca per la SLA (grants EXOMEFALS and NOVALS) and the Italian Ministry of Health (grant GR-2011-02347820 - IRisALS). R.L. McLaughlin was supported by Science Foundation Ireland and the MND Association of England, Wales and Northern Ireland. O.H. is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland. P.J.S. is supported as an NIHR Senior Investigator (NF-SI-0512-10082). P.J.S. and J. Kirby are supported by the Sheffield NIHR Biomedical Research Centre for Translational Neuroscience (IS-BRC-1215-20017). A. Chiò receives research support from the Italian Ministry of Health (Ricerca Finalizzata), Regione Piemonte (Ricerca Finalizzata), University of Turin, Fondazione Vialli e Mauro onlus, and the European Commission (Health Seventh Framework Programme). P.M.A. is supported by research grants from the Swedish Brain Foundation, the Swedish Science Council, the Knut and Alice Wallenberg Foundation, the Bertil Hållsten Foundation, the Ulla-Carin Lindquist Foundation, the Neuroförbundet Association, the Torsten and Ragnar Söderberg Foundation, the Stratneuro Initiative, and Västerbotten County Council. R.B. received funding support from NINDS/NS061867 and Target ALS. R.H.B.J. received funding from the Angel Fund, Project ALS/P2ALS, and the ALS Therapy Alliance. E. Rogaeva received funding support from the Canadian Consortium on Neurodegeneration in Aging. L. Myllykangas received funding support from Helsinki University Hospital and the Academy of Finland (grant 294817). P.T. received funding support from Helsinki University Hospital and the Sigrid Jusélius Foundation. J.D.G. received funding support from the ALS Association and Muscular Dystrophy Association. Additional funding was provided by the NIH/NINDS (R01NS073873, J.E.L.), the ALS Association (N.T., V.S., C.E.S., R.H.B.J., and J.E.L.), and the MND Association (N.T., V.S., C.E.S., and J.E.L.). J. Kaye, S.F., S.K.W., A.L., E.F., C.N.S., L.M.T., J.E.V.E., and J.D.R. received funding through NeuroLINCS (NIH U54 NS091046). The sequencing activities at NYGC were additionally supported by the TOW Foundation. The CReATe consortium (U54NS092091) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. This consortium is funded through collaboration between NCATS and the NINDS. The Target ALS Human Postmortem Tissue Core received funding support from Target ALS (grant 90072272). The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the United States National Institute on Aging (contracts 263 MD 9164 and 263 MD 821336), the InCHIANTI follow-up 1 (2001–2003) was funded by the United States National Institute on Aging (contracts N.1-AG-1-1 and N.1-AG-1-2111), and the InCHIANTI follow-ups 2 and 3 studies (2004–2010) were financed by the United States National Institute on Aging (contract N01-AG-5-0002). This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02); by the National Institute of Neurological Disorders and Stroke; and by Merck & Co., Inc. The work was also supported by the Center for Disease Control and Prevention, the Muscular Dystrophy Association, Microsoft Research, the Packard Center for ALS Research at Johns Hopkins, the ALS Association, UK MND Association, Medical Research Council (MRC) UK, Wellcome Trust/MRC Joint Call in Neurodegeneration Award, MRC Neuromuscular Centre, UK National Institute for Health Research Biomedical Research Unit, Italian Health Ministry (Ricerca Sanitaria Finalizzata 2007), Fondazione Vialli e Mauro Onlus, Compagnia di San Paolo, and European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867. Role of the sponsors: the sponsors did not participate in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. We thank the patients and research subjects who contributed samples for this study. This study used DNA samples and clinical data from the Target ALS Human Postmortem Tissue Core, the NINDS Repository at Coriell, the North East ALS (NEALS) Consortium Biorepository, the New York Brain Bank-The Taub Institute, Columbia University, Department of Veterans Affairs Biorepository Brain Bank (grant #BX002466; C.B.B.), the Baltimore Longitudinal Study of Aging (BLSA) and the Johns Hopkins University Alzheimer's Disease Research Center, the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, and the Australian MND DNA Bank. We also thank Crystal Pacut, Blake Swihart, and Jayna Duell, RN for assistance in study coordination (S.A.G.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, Maryland (http://hpc.nih.gov), and the Massachusetts Green High Performance Computing Center at the University of Massachusetts Medical School (https://www.mghpcc.org). This study also used genotype and clinical data from the Wellcome Trust Case Control Consortium.

Funding Information:
The ALS Association (ALSA) provided funding support to Project MinE ( 15-LGCA-235 ), the NYGC ALS Consortium ( 15-LGCA-234 ), the CReATe Consortium ( 17-LGCA-331 ), the GTAC Consortium ( 16-LGCA-310 ), the Target ALS Human Postmortem Tissue Core ( 16-LGCA-308 ), and NeuroLINCS, an NIH-funded collaborative effort. P.V.D. is a senior investigator of FWO-Vlaanderen. Project MinE Belgium has been supported by ALS liga België , Flanders Innovation & Enterpreneurship (IWT grant Project MinE ), the Belgian National Lottery , and a grant from Opening the Future Fund (KU Leuven). W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders and ERC (grant agreement no. 340429 ). Additional funding support includes NINDS R35 NS097261 (R.R.) and P01NS084974 (R.R. and K.B.B.). A.N.B. thanks the Suna and Inan Kirac Foundation , Istanbul, TR for its generous support of the Neurodegeneration Research Laboratory throughout this study. Funding for this work was provided by the Heaton-Ellis Trust , the Middlemass Family , Motor Neurone Disease Association , Medical Research Council , Medical Research Foundation , the Psychiatry Research Trust of the Institute of Psychiatry , Guy's and St Thomas' Charity , the Wellcome Trust , and the Noreen Murray Foundation (C.E.S.). This work was also supported by the UK Dementia Research Institute , which is funded by the Medical Research Council , Alzheimer's Society , and Alzheimer’s Research UK (C.E.S.). The salary for B.N.S. was funded by the Medical Research Foundation (MRF) ( MRF-060-0003-RG-SMITH ). P.C.S. was supported through the auspices of Dr. H. Robert Horvitz (Massachusetts Institute of Technology), an Investigator of the Howard Hughes Institute. Support for this work came from the Department of Veterans Affairs and NIH ( P30AG13846 ) to N.W.K. I.P.B. is supported by the Motor Neurone Disease Research Institute of Australia and the National Health and Medical Research Council of Australia ( 1107644 and 1095215 ). P.F. is supported by an MRC/MNDA LEWF and by NIHR UCLH BRC . Research support from NIH/NIEHS ( K23ES027221 ), the ALS Association , Target ALS , and Cytokinetics was provided to S.A.G. M. Cudkowicz was awarded funding from ALS Finding a Cure . N.T., C. Tiloca, C.G., V.S., and J.E.L. received research support from AriSLA – Fondazione Italiana di Ricerca per la SLA (grants EXOMEFALS and NOVALS ) and the Italian Ministry of Health (grant GR-2011-02347820 - IRisALS ). R.L. McLaughlin was supported by Science Foundation Ireland and the MND Association of England, Wales and Northern Ireland . O.H. is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland . P.J.S. is supported as an NIHR Senior Investigator ( NF-SI-0512-10082 ). P.J.S. and J. Kirby are supported by the Sheffield NIHR Biomedical Research Centre for Translational Neuroscience ( IS-BRC-1215-20017 ). A. Chiò receives research support from the Italian Ministry of Health (Ricerca Finalizzata), Regione Piemonte (Ricerca Finalizzata), University of Turin , Fondazione Vialli e Mauro onlus , and the European Commission (Health Seventh Framework Programme). P.M.A. is supported by research grants from the Swedish Brain Foundation , the Swedish Science Council , the Knut and Alice Wallenberg Foundation , the Bertil Hållsten Foundation , the Ulla-Carin Lindquist Foundation , the Neuroförbundet Association , the Torsten and Ragnar Söderberg Foundation , the Stratneuro Initiative , and Västerbotten County Council . R.B. received funding support from NINDS/NS061867 and Target ALS . R.H.B.J. received funding from the Angel Fund , Project ALS/P2ALS , and the ALS Therapy Alliance . E. Rogaeva received funding support from the Canadian Consortium on Neurodegeneration in Aging . L. Myllykangas received funding support from Helsinki University Hospital and the Academy of Finland (grant 294817 ). P.T. received funding support from Helsinki University Hospital and the Sigrid Jusélius Foundation . J.D.G. received funding support from the ALS Association and Muscular Dystrophy Association . Additional funding was provided by the NIH/NINDS ( R01NS073873 , J.E.L.), the ALS Association (N.T., V.S., C.E.S., R.H.B.J., and J.E.L.), and the MND Association (N.T., V.S., C.E.S., and J.E.L.). J. Kaye, S.F., S.K.W., A.L., E.F., C.N.S., L.M.T., J.E.V.E., and J.D.R. received funding through NeuroLINCS ( NIH U54 NS091046 ). The sequencing activities at NYGC were additionally supported by the TOW Foundation . The CReATe consortium ( U54NS092091 ) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. This consortium is funded through collaboration between NCATS and the NINDS. The Target ALS Human Postmortem Tissue Core received funding support from Target ALS (grant 90072272 ). The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” ( ICS110.1/RF97.71 ) by the Italian Ministry of Health and in part by the United States National Institute on Aging (contracts 263 MD 9164 and 263 MD 821336 ), the InCHIANTI follow-up 1 (2001–2003) was funded by the United States National Institute on Aging (contracts N.1-AG-1-1 and N.1-AG-1-2111 ), and the InCHIANTI follow-ups 2 and 3 studies (2004–2010) were financed by the United States National Institute on Aging (contract N01-AG-5-0002 ). This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging ( Z01-AG000949-02 ); by the National Institute of Neurological Disorders and Stroke ; and by Merck & Co., Inc. . The work was also supported by the Center for Disease Control and Prevention , the Muscular Dystrophy Association , Microsoft Research , the Packard Center for ALS Research at Johns Hopkins , the ALS Association , UK MND Association , Medical Research Council (MRC) UK , Wellcome Trust/MRC Joint Call in Neurodegeneration Award , MRC Neuromuscular Centre , UK National Institute for Health Research Biomedical Research Unit , Italian Health Ministry (Ricerca Sanitaria Finalizzata 2007), Fondazione Vialli e Mauro Onlus , Compagnia di San Paolo , and European Community’s Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867 . Role of the sponsors: the sponsors did not participate in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. We thank the patients and research subjects who contributed samples for this study. This study used DNA samples and clinical data from the Target ALS Human Postmortem Tissue Core, the NINDS Repository at Coriell, the North East ALS (NEALS) Consortium Biorepository, the New York Brain Bank-The Taub Institute, Columbia University, Department of Veterans Affairs Biorepository Brain Bank (grant # BX002466 ; C.B.B.), the Baltimore Longitudinal Study of Aging (BLSA) and the Johns Hopkins University Alzheimer’s Disease Research Center, the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, and the Australian MND DNA Bank. We also thank Crystal Pacut, Blake Swihart, and Jayna Duell, RN for assistance in study coordination (S.A.G.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, Maryland ( http://hpc.nih.gov ), and the Massachusetts Green High Performance Computing Center at the University of Massachusetts Medical School ( https://www.mghpcc.org ). This study also used genotype and clinical data from the Wellcome Trust Case Control Consortium.

Funding Information:
J.D.B. is a consultant to Neuraltus Pharmaceuticals and Denali Therapeutics, and held a research fellow position funded by Voyager Therapeutics. M. Cudkowicz has been a consultant for Eli Lilly and Company, Mitsubishi Tanabe Pharma America (MT Pharma America), Denali Therapeutics, Karyopharm Therapeutics, and Cytokinetics. S.A.G. has served as a consultant for and received research support from Cytokinetics. O.H. has received speaking honoraria from Novartis, Biogen Idec, Sanofi Aventis, and Merck-Serono and has been a member of advisory panels for Biogen Idec, Allergen, Ono Pharmaceuticals, Novartis, Cytokinetics, and Sanofi Aventis. O.H. serves as Editor-in-Chief of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. L.H.v.d.B. serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen, and Cytokinetics and serves on the editorial board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration and the Journal of Neurology, Neurosurgery, and Psychiatry. J.H.V. reports that his institute received consultancy fees from Vertex Pharmaceuticals. A. Chiò serves on scientific advisory boards for Biogen Idec, Cytokinetics, Italfarmaco, and Neuraltus. P.M.A. serves on advisory board panels for Biogen and Orphazyme. V.S. serves as a consultant for Cytokinetics.

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

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

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