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Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

SUBMITTER: Cirulli ET

PROVIDER: S-EPMC4437632 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Cirulli Elizabeth T ET Lasseigne Brittany N BN Petrovski Slavé S Sapp Peter C PC Dion Patrick A PA Leblond Claire S CS Couthouis Julien J Lu Yi-Fan YF Wang Quanli Q Krueger Brian J BJ Ren Zhong Z Keebler Jonathan J Han Yujun Y Levy Shawn E SE Boone Braden E BE Wimbish Jack R JR Waite Lindsay L LL Jones Angela L AL Carulli John P JP Day-Williams Aaron G AG Staropoli John F JF Xin Winnie W WW Chesi Alessandra A Raphael Alya R AR McKenna-Yasek Diane D Cady Janet J Vianney de Jong J M B JM Kenna Kevin P KP Smith Bradley N BN Topp Simon S Miller Jack J Gkazi Athina A Al-Chalabi Ammar A van den Berg Leonard H LH Veldink Jan J Silani Vincenzo V Ticozzi Nicola N Shaw Christopher E CE Baloh Robert H RH Appel Stanley S Simpson Ericka E Lagier-Tourenne Clotilde C Pulst Stefan M SM Gibson Summer S Trojanowski John Q JQ Elman Lauren L McCluskey Leo L Grossman Murray M Shneider Neil A NA Chung Wendy K WK Ravits John M JM Glass Jonathan D JD Sims Katherine B KB Van Deerlin Vivianna M VM Maniatis Tom T Hayes Sebastian D SD Ordureau Alban A Swarup Sharan S Landers John J Baas Frank F Allen Andrew S AS Bedlack Richard S RS Harper J Wade JW Gitler Aaron D AD Rouleau Guy A GA Brown Robert R Harms Matthew B MB Cooper Gregory M GM Harris Tim T Myers Richard M RM Goldstein David B DB

Science (New York, N.Y.) 20150219 6229

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphoryla ...[more]

PMID: 25700176

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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

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Publications

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

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