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Author Notes:

Correspondence should be addressed to J.H.V. (j.h.veldink@umcutrecht.nl)

See publication for full list of author contributions.

We acknowledge all of the study participants and our collaborators for enabling this study by graciously providing samples for this study.

We thank people with MND, their families and control individuals for their participation in this project.

The authors declare no competing financial interests.

Subjects:

Research Funding:

See publication for full funding statement.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • NIMA-FAMILY KINASE
  • WHOLE-GENOME
  • SEQUENCING DATA
  • PRIMARY CILIA
  • DNA-DAMAGE
  • MUTATIONS
  • DISEASE
  • IDENTIFICATION
  • ASSOCIATION
  • ALS

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

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Journal Title:

Nature Genetics

Volume:

Volume 48, Number 9

Publisher:

, Pages 1037-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (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.

Copyright information:

© 2016 Nature America, Inc. All rights reserved.

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