Dataset Information

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.

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.

SUBMITTER: Kenna KP

PROVIDER: S-EPMC5560030 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.

Kenna Kevin P KP van Doormaal Perry T C PT Dekker Annelot M AM Ticozzi Nicola N Kenna Brendan J BJ Diekstra Frank P FP van Rheenen Wouter W van Eijk Kristel R KR Jones Ashley R AR Keagle Pamela P Shatunov Aleksey A Sproviero William W Smith Bradley N BN van Es Michael A MA Topp Simon D SD Kenna Aoife A Miller Jack W JW Fallini Claudia C Tiloca Cinzia C McLaughlin Russell L RL Vance Caroline C Troakes Claire C Colombrita Claudia C Mora Gabriele G Calvo Andrea A Verde Federico F Al-Sarraj Safa S King Andrew A Calini Daniela D de Belleroche Jacqueline J Baas Frank F van der Kooi Anneke J AJ de Visser Marianne M Ten Asbroek Anneloor L M A AL Sapp Peter C PC McKenna-Yasek Diane D Polak Meraida M Asress Seneshaw S Muñoz-Blanco José Luis JL Strom Tim M TM Meitinger Thomas T Morrison Karen E KE Lauria Giuseppe G Williams Kelly L KL Leigh P Nigel PN Nicholson Garth A GA Blair Ian P IP Leblond Claire S CS Dion Patrick A PA Rouleau Guy A GA Pall Hardev H Shaw Pamela J PJ Turner Martin R MR Talbot Kevin K Taroni Franco F Boylan Kevin B KB Van Blitterswijk Marka M Rademakers Rosa R Esteban-Pérez Jesús J García-Redondo Alberto A Van Damme Phillip P Robberecht Wim W Chio Adriano A Gellera Cinzia C Drepper Carsten C Sendtner Michael M Ratti Antonia A Glass Jonathan D JD Mora Jesús S JS Basak Nazli A NA Hardiman Orla O Ludolph Albert C AC Andersen Peter M PM Weishaupt Jochen H JH Brown Robert H RH Al-Chalabi Ammar A Silani Vincenzo V Shaw Christopher E CE van den Berg Leonard H LH Veldink Jan H JH Landers John E JE

Nature genetics 20160725 9

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 c ...[more]

PMID: 27455347

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Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals.WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5?×?10-5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran-Mantel-Haenszel test to compare gene-level variant counts in cases vs controls.No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p?=?8.3?×?10-12), SOD1 (p?=?8.9?×?10-9) and NEK1 (p?=?1.1?×?10-9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p?=?0.04 and p?=?7?×?10-3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p?=?0.14).While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans.

Dataset Information

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.

Publications

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.

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