NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
Files
Publication date
2016-07-25
Authors
Kenna, Kevin P.
van Doormaal, Perry T C
Dekker, Annelot
Ticozzi, Nicola
Kenna, Brendan J
Diekstra, Frank P.
van Rheenen, Wouter
Van Eijk, Kristel R.
Jones, Ashley R
Keagle, Pamela
Editors
Advisors
Supervisors
Document Type
Article
Metadata
Show full item recordCollections
License
taverne
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.
Keywords
Taverne, Journal Article, Comparative Study
Citation
Kenna, K P, van Doormaal, P T C, Dekker, A M, Ticozzi, N, Kenna, B J, Diekstra, F P, van Rheenen, W, van Eijk, K R, Jones, A R, Keagle, P, Shatunov, A, Sproviero, W, Smith, B N, van Es, M A, Topp, S D, Kenna, A, Miller, J W, Fallini, C, Tiloca, C, McLaughlin, R L, Vance, C, Troakes, C, Colombrita, C, Mora, G, Calvo, A, Verde, F, Al-Sarraj, S, King, A, Calini, D, de Belleroche, J, Baas, F, van der Kooi, A J, de Visser, M, Ten Asbroek, A L M A, Sapp, P C, McKenna-Yasek, D, Polak, M, Asress, S, Muñoz-Blanco, J L, Strom, T M, Meitinger, T, Morrison, K E, Lauria, G, Williams, K L, Leigh, P N, Nicholson, G A, Blair, I P, Leblond, C S, van den Berg, L H, Veldink, J H & SLAGEN Consortium 2016, 'NEK1 variants confer susceptibility to amyotrophic lateral sclerosis', Nature Genetics, vol. 48, no. 9, pp. 1037–1042. https://doi.org/10.1038/ng.3626