NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Kevin P. Kenna, Perry T C van Doormaal, Annelot M. Dekker, N. Ticozzi, Brendan J. Kenna, Frank P. Diekstra, Wouter Van Rheenen, Kristel R. van Eijk, R. A. Jones, Pamela J. Keagle, Aleksey Shatunov, William Sproviero, Bradley N. Smith, Michael A. van Es, S.D. Topp, Margaret A. Kenna, William J. Miller, Claudia Fallini, C. Tiloca, Russell L. McLaughlinCarl Vance, Claire Troakes, C. Colombrita, G. Mora, Felipe A. Calvo, Federico Verde, S. Al-Sarraj, A. King, Daniela Calini, Jacqueline De Belleroche, Annette F. Baas, Anneke J. Van Der Kooi, M. De Visser, Anneloor L M A ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, M. Polak, Seneshaw Asress, JoséLuis L. Muñoz-Blanco, T. M. Strom, T. Meitinger, Karen E. Morrison, G. Lauria, Kelly L. Williams, P. Nigel Leigh, A. G. Nicholson, Ian P. Blair, Claire S. Leblond, Patrick A. Dion, Guy A. Rouleau, Hardev Pall, P. J. Shaw, Martin R. Turner, K. Talbot, F. Taroni, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Jesús Esteban-Pérez, A. García-Redondo, Philip van Damme, Wim Robberecht, A. Di Chio, C. Gellera, Carsten Drepper, Michael Sendtner, A. Ratti, Jonathan D. Glass, Jesus S. Mora, Ayse N. Basak, Orla Hardiman, A. C. Ludolph, P. M. Andersen, Jochen H. Weishaupt, R. H. Brown, Ammar Al-Chalabi, V. Silani, E. C. Shaw, Leonard H. Van Den Berg, Jan H. Veldink, J.E. Landers, Giacomo Pietro Comi, Roberto Del Bo, Stefania Paola Corti

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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.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. © 2016 Nature America, Inc. All rights reserved.
Original languageEnglish
Pages (from-to)1037-1042
Number of pages6
JournalNature Genetics
Issue number9
Publication statusPublished - 2016

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