☆ 4.8 Article

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

NATURE GENETICS (2016)

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Journal

NATURE GENETICS
Volume 48, Issue 9, Pages 1037-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/ng.3626

Keywords

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Categories

Genetics & Heredity

Funding

  1. US National Institutes of Health (NU)/National Institutc of Neurological Disorders and Stroke (MINDS) [R01 N5073873]
  2. American ALS Association
  3. Motor Neuron Disease (HIND) Association
  4. Angel Fund
  5. Project ALS/P2AIS
  6. ALS Therapy Alliance
  7. Netherlands ALS Foundation
  8. ALS Lisa Belgium
  9. Suna and Ivan Kirac Foundation
  10. Netherlands Organization for Hcalth Research and Development
  11. National Health and Medical Research Council (NHMRC) of Australia [1095215, 1107644]
  12. Netherlands Organization for Health Research and-Development
  13. EU Joint Programme - Neuro degenerative Disease Research (JPND) project
  14. JPND
  15. National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London
  16. Maudsley NHS Foundation Trust
  17. King's College London
  18. European Community's Health Seventh Framework Programme (FP7) [259867]
  19. UK National DNA Bank for MND Research
  20. MND Association
  21. Wellcome Trust
  22. I.R.C.C.S. Istituto Auxologico Italiano
  23. Healthcare Research of the Italian Ministry of Health [RepeatALS 2013]
  24. Italian Ministry of Health [GR-2011-02347820 - IRisALS]
  25. Flemish agency
  26. Interuniversity Attraction Poles (IUAP) program P7/16 of the Belgian Federal Science Policy Office
  27. FWO-Vlaanderen [E-RARE-2]
  28. ERA-Net for Research on Rare Diseases (PYRAMID)
  29. EU JPND project (STRENGTH)
  30. FWO Vlaanderen
  31. Belgian ALS liga
  32. MND Australia
  33. NHMRC fellowship [1092023]
  34. Canadian Institute of Health Research (CHIR)
  35. PALS [208973]
  36. Muscular Dystrophy Association
  37. ALS society of Canada
  38. E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
  39. Laevers Fund for ALS Research
  40. ALS Liga Belgic
  41. fund 'Een Hart voor ALS'
  42. fund 'Opening the Future
  43. European Research Council
  44. European's Seventh Framework Programme (EP7)/ERC [340429]
  45. Geneeskundige Stichting Koningin Elisabeth
  46. Deutsche Forschungsgemeinschaft [SE697/4-1]
  47. BMBF Energl
  48. Deutsche Gesellschaft far Muskelkranke [He 2/2]
  49. German Federal Ministry of Education and Research (JPND STRENGTH consortium
  50. German network for ALS research MND-NET)
  51. Charcot Foundation for ALS Research
  52. virtual Helmholtz Institute RNA-Dysmetabolismus in ALS and FTD
  53. DFG Swabian ALS Registry
  54. Italian Ministry of Health (Ricerca Sanitaria Finalizzata) [RF-2010-2309849, CR-2010-2320550]
  55. European Community's Health Seventh Framework Programme (FP7)
  56. Joint Programme - Neurodegencrative Disease Research (Italian Ministry of Education and University) (Sophia, and Strength Projects)
  57. Italian Ministry of Health (Ricerca Sanitaria Finalizzata)
  58. FUNDELA - Spanish Foundation
  59. ISCIII Carlos III Institute / Fond de Investigacion Sanitaria of Spain [PT10/00092, PT14/00088]
  60. ADELA ALS Spanish Association
  61. SURF Foundation
  62. Alzheimer's Disease Sequencing Project (ADSP) [phs000572.v7.p4]
  63. National Human Genome Research Institute (NHGRI)
  64. Large Scale Sequencing Centers (LSSC)
  65. Alzheimer's Disease Genetics Consortium (ADGC)
  66. National Institute on Aging (NIA) [U01 AG032984]
  67. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)
  68. NIA [R01 AG033193]
  69. National Heart, Lung, and Blood Institute(NHLBI)
  70. other NIH institutes and other foreign governmental and nongovernmental organizations
  71. Adult Changes in Thought (ACT)
  72. Alzheimer's Disease Centers (ADC)
  73. Chicago Health and Aging Project (CHAP)
  74. Memory and Aging Project (MAP)
  75. Mayo Clinic
  76. Mayo Parkinson's Disease controls
  77. University of Miami
  78. Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE)
  79. National Cell Repository for Alzheimer's disease (NCRAD)
  80. National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA-LOAD)
  81. Religious Orders Study (ROS)
  82. Texas Alzheimer's Research and Care Consortium (TARC)
  83. Vanderbilt University/Case Western Reserve university VAN/CWRU)
  84. Washington Heights-Inwood Columbia Agiisg Project (WHICAP)
  85. Washington University Sequencing Project (WUSP)
  86. Columbia University Hispanic-Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA)
  87. University of Toronto
  88. Genetic Differences (GD)
  89. CHARGE cohorts [5RC2HL102419, HL105756]
  90. NHLBI [HH5N268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100090C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]
  91. Austrian Stroke Prevention Study (ASPS)
  92. Cardiovascular Health Study (CHS)
  93. Erasmus Rucphen Family Study (ERE)
  94. Framingham Heart Study (FHS)
  95. Rutter-dam Study (RS)
  96. Human Genome Sequencing Center at the Baylor College of Medicine [U54HG003273]
  97. Broad Institute Ccnome Center [U54HG003067]
  98. Washington University Genome Institute [U54HG003079]
  99. National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University [U24AG0218861]
  100. NIA
  101. NIA-Alzheimer's Disease Centers (ADCs)
  102. National Alzheimer's Coordinating Center (NACC) [U01AG016976]
  103. National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania [U24AG041689]
  104. NLA
  105. NIH
  106. private US organizations
  107. [UF1AG047133]
  108. [U01AG049505]
  109. [U01AG049506]
  110. [U01AG049507]
  111. [U01AG049308]
  112. Medical Research Council [G0900688, MR/L016397/1, MR/K01014X/1, G0600974, MR/K000039/1, MC_G1000733, G1100695, MR/L501529/1] Funding Source: researchfish
  113. Medical Research Foundation [MRF-060-0003-RG-SMITH] Funding Source: researchfish
  114. Motor Neurone Disease Association [Jones/Oct15/958-799, Turner/Jan13/944-795] Funding Source: researchfish
  115. National Institute for Health Research [NF-SI-0512-10082] Funding Source: researchfish
  116. MRC [G1100695, G0600974, MC_G1000733, G0900688, MR/K01014X/1, MR/K000039/1, MR/L016397/1] Funding Source: UKRI
  117. National Health and Medical Research Council of Australia [1107644, 1092023] Funding Source: NHMRC

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To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

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