Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

• Type of Material: Article
• Authors: Ahmad Al Khleifat, Kings College London; Alfredo Iacoangeli, Kings College London; Ashley R Jones, Kings College London; Joke JFA van Vugt, Utrecht University; Matthieu Moisse, KU Leuven—University of Leuven; Aleksey Shatunov, North-Eastern Federal University; Ramona AJ Zwamborn, Utrecht University; Rick AA van der Spek, Utrecht University; Johnathan Cooper-Knock, University of Sheffield; Simon Topp, Kings College London; Wouter van Rheenen, Utrecht University; Brendan Kenna, Utrecht University; Kristel R Van Eijk, Utrecht University; Kevin Kenna, Utrecht University; Ross Byrne, Trinity College Dublin; Victoria López, Instituto de Salud Carlos III; Sarah Opie-Martin, Kings College London; Atay Vural, Koc University; Yolanda Campos, Instituto de Salud Carlos III; Markus Weber, Koc University; Bradley Smith, Kings College London; Isabella Fogh, Kings College London; Vincenzo Silani, IRCCS Istituto Auxologico Italiano; Kareen E Morrison, Queens University Belfast; Richard Dobson, Kings College London; Michael A van Es, Utrecht University; Russell L McLaughlin, Trinity College Dublin; Patrick Vourc'h, Centre SLA, CHRU de Tours; Adriano Chio, University of Torino, Turin; Philippe Corcia, CHRU de Tours; Mamede de Carvalho, University of Lisbon; Marc Gotkine, Hebrew University of Jerusalem; Monica Povedano Panades, Hospital Universitari de Bellvitge; Jesus S Mora, Hospital San Rafael; Pamela J Shaw, University of Sheffield; John E Landers, University of Massachusetts Worcester; Christopher E Shaw, Kings College London; Nazli Basak, Koc University; Orla Hardiman, Trinity College Dublin; Wim Robberecht, KU Leuven—University of Leuven; Philip Van Damme, KU Leuven—University of Leuven; Leonard H van den Berg, Utrecht University; Jan H Veldink, Utrecht University; Ammar Al-Chalabi, Kings College London
• Language: English
• Date: 2022-12-15
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Al Khleifat, Iacoangeli, Jones, van Vugt, Moisse, Shatunov, Zwamborn, van der Spek, Cooper-Knock, Topp, van Rheenen, Kenna, Van Eijk, Kenna, Byrne, López, Opie-Martin, Vural, Campos, Weber, Smith, Fogh, Silani, Morrison, Dobson, van Es, McLaughlin, Vourc’h, Chio, Corcia, de Carvalho, Gotkine, Panades, Mora, Shaw, Landers, Glass, Shaw, Basak, Hardiman, Robberecht, Van Damme, van den Berg, Veldink and Al-Chalabi.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fncel.2022.1050596
• Title of Journal or Parent Work: FRONTIERS IN CELLULAR NEUROSCIENCE
• Volume: 16
• Start Page: 1050596
• End Page: 1050596
• Grant/Funding Information: AAK was funded by ALS Association Milton Safenowitz Research Fellowship (grant number 22-PDF-609. doi: 10.52546/pc.gr.150909), The Motor Neurone Disease Association (MNDA) Fellowship (Al Khleifat/Oct21/975-799), The Darby Rimmer Foundation, and The NIHR Maudsley Biomedical Research Centre.; The collaboration project was co-funded by the PPP Allowance made available by Health∼Holland, Top Sector Life Sciences and Health, to stimulate public-private partnerships. Project MinE Belgium was supported by a grant from IWT, the Belgian ALS Liga and a grant from Opening the Future Fund (KU Leuven). PVD holds a senior clinical investigatorship of FWO-Vlaanderen and was supported by E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds “Een Hart voor ALS,” “Laeversfonds voor ALS Onderzoek,” and the “Valéry Perrier Race against ALS Fund”. RM was supported by Science Foundation Ireland (17/CDA/4737). MinE USA was funded by the US ALS Association.; This project was also funded by the MND Association and the Wellcome Trust. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND–www.jpnd.eu [United Kingdom, Medical Research Council (MR/L501529/1 and MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)].; AA-C was a NIHR Senior Investigator. CS and AA-C received salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King’s College London. The work leading up to this publication was funded by the European Community’s Health Seventh Framework Program (FP7/2007–2013; grant agreement number 259867) and Horizon 2020 Program (H2020-PHC-2014-two-stage; grant agreement number 633413). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 772376–EScORIAL.
• Keywords: Neurosciences & Neurology; ELONGATION; MND-motor neuron disorders; Science & Technology; whole genome sequence (WGS); ALS; amyotrophic lateral sclerosis (ALS); RISK; Life Sciences & Biomedicine; GENDER; ASSOCIATION; genomics; bigdata; CANCER; TUMORS; Neurosciences; telomere-genetics
• Research Categories: Biology, General

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS. Methods: Samples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression. Results: There were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10−12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10−7). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10−4). Discussion: Although telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.