Letter. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Kevin P. Kenna, Perry T.C. van Doormaal, Annelot M. Dekker, Nicola Ticozzi, Brendan J. Kenna, Frank P. Diekstra, Wouter van Rheenen, Kristel R. van Eijk, Ashley R. Jones, Pamela Keagle, Aleksey Shatunov, William Sproviero, Bradley N. Smith, Michael A. van Es, Simon D. Topp, Aoife Kenna, Jack W. Miller, Claudia Fallini, Cinzia Tiloca, Russell L. McLaughlinCaroline Vance, Claire Troakes, Claudia Colombrita, Gabriele Mora, Andrea Calvo, Federico Verde, Safa Al-Sarraj, Andrew King, Daniela Calini, Jacqueline de Belleroche, Frank Baas, Anneke J. van der Kooi, Marianne de Visser, Anneloor L.M.A. ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, José Luis Muñoz-Blanco, Tim M. Strom, Thomas Meitinger, Karen E. Morrison, Sandra D'Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Giuseppe Lauria, Kelly L. Williams, P Nigel Leigh, Garth A. Nicholson, Ian P. Blair, Claire S. Leblond, Patrick A. Dion, Guy A. Rouleau, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Jesús Esteban-Pérez, Alberto García-Redondo, Phillip Van Damme, Wim Robberecht, Adriano Chio, Cinzia Gellera, Carsten Drepper, Michael Sendtner, Antonia Ratti, Jonathan D. Glass, Jesús S. Mora, Nazli A. Basak, Orla Hardiman, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, Robert H. Brown, Ammar Al-Chalabi, Vincenzo Silani, Christopher E. Shaw, Leonard H. van den Berg, Jan H. Veldink, John E. Landers

Research output: Contribution to journalArticlepeer-review

108 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)1037-1042
Number of pages6
JournalNature Genetics
Issue number9
Early online date25 Jul 2016
Publication statusPublished - 01 Sep 2016

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