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 Jones, Pamela J. Keagle, Aleksey Shatunov, William Sproviero, Bradley N. Smith, Michael A. van Es, Simon Topp, Aoife Kenna, Jack Miller, Claudia Fallini, Cinzia Tiloca, Russell L. McLaughlinCaroline Vance, Claire Troakes, Claudia Colombrita, Gabriele Mora, Andrea Calvo, Federico Verde, S. Al-Sarraj, Andrew King, Daniela Calini, Jacqueline De Belleroche, Frank Baas, Anneke J. Van Der Kooi, M. 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, Giuseppe Lauria, Giuseppe Lauria, 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, Franco Taroni, Marka Van Blitterswijk, Rosa Rademakers, Jesús Esteban-Pérez, Alberto Garcia Redondo, Philip van Damme, Wim Robberecht, Adriano Chiò, Cinzia Gellera, Cinzia Gellera, Michael Sendtner, Antonia Ratti, Antonia Ratti, Jesus S. Mora, Nazli A. Basak, Orla Hardiman, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, Robert H. Brown, Ammar Al-Chalabi, Vincenzo Silani, Vincenzo Silani, Leonard H. Van Den Berg, Jan Veldink, John Landers

Research output: Contribution to journalArticlepeer-review


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
JournalNature Genetics
Publication statusPublished - 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics


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