| Literature DB >> 27455347 |
Kevin P Kenna1, Perry T C van Doormaal2, Annelot M Dekker2, Nicola Ticozzi3,4, Brendan J Kenna1, Frank P Diekstra2, Wouter van Rheenen2, Kristel R van Eijk2, Ashley R Jones5, Pamela Keagle1, Aleksey Shatunov5, William Sproviero5, Bradley N Smith5, Michael A van Es2, Simon D Topp5, Aoife Kenna1, Jack W Miller5, Claudia Fallini1, Cinzia Tiloca3,6, Russell L McLaughlin7, Caroline Vance5, Claire Troakes5, Claudia Colombrita3,4, Gabriele Mora8, Andrea Calvo9, Federico Verde3,4, Safa Al-Sarraj5, Andrew King5, Daniela Calini3, Jacqueline de Belleroche10, Frank Baas11, Anneke J van der Kooi12, Marianne de Visser12, Anneloor L M A Ten Asbroek11, Peter C Sapp1, Diane McKenna-Yasek1, Meraida Polak13, Seneshaw Asress13, José Luis Muñoz-Blanco14, Tim M Strom15, Thomas Meitinger16, Karen E Morrison17, Giuseppe Lauria18, Kelly L Williams19, P Nigel Leigh20, Garth A Nicholson19,21, Ian P Blair19, Claire S Leblond22, Patrick A Dion22, Guy A Rouleau22, Hardev Pall23,24, Pamela J Shaw25, Martin R Turner25, Kevin Talbot25, Franco Taroni26, Kevin B Boylan27, Marka Van Blitterswijk28, Rosa Rademakers28, Jesús Esteban-Pérez29,30, Alberto García-Redondo29,30, Phillip Van Damme31,32, Wim Robberecht31,32, Adriano Chio9, Cinzia Gellera26, Carsten Drepper33,34, Michael Sendtner33, Antonia Ratti3,4, Jonathan D Glass13, Jesús S Mora35, Nazli A Basak36, Orla Hardiman7, Albert C Ludolph37, Peter M Andersen38, Jochen H Weishaupt37, Robert H Brown1, Ammar Al-Chalabi5, Vincenzo Silani3,4, Christopher E Shaw5, Leonard H van den Berg2, Jan H Veldink2, John E Landers1.
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.Entities:
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Year: 2016 PMID： 27455347 PMCID： PMC5560030 DOI： 10.1038/ng.3626
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 41.307