NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
Authors
Kenna, Kevin P.van Doormaal, Perry T. C.
Dekker, Annelot M.
Ticozzi, Nicola
Kenna, Brendan J.
Keagle, Pamela J.
Kenna, Aoife
Fallini, Claudia
Sapp, Peter C.
McKenna-Yasek, Diane
Brown, Robert H. Jr.
Silani, Vincenzo
Shaw, Christopher E.
van den Berg, Leonard H.
Veldink, Jan H.
Landers, John E.
UMass Chan Affiliations
Department of NeurologyDocument Type
Journal ArticlePublication Date
2016-07-25
Metadata
Show full item recordAbstract
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.Source
Nat Genet. 2016 Jul 25. doi: 10.1038/ng.3626. [Epub ahead of print]DOI
10.1038/ng.3626.Permanent Link to this Item
http://hdl.handle.net/20.500.14038/37774PubMed ID
27455347Notes
Full author list omitted for brevity. For the full list of authors, see article.
Related Resources
Link to article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/ng.3626.