| Title: |
Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data |
| Authors: |
Al Khleifat, Ahmad; Iacoangeli, Alfredo; Jones, Ashley R; van Vugt, Joke J F A; Moisse, Matthieu; Shatunov, Aleksey; Zwamborn, Ramona A J; van der Spek, Rick A A; Cooper-Knock, Johnathan; Topp, Simon; Van Rheenen, Wouter; Kenna, Brendan; van Eijk, Kristel R; Kenna, Kevin; Byrne, Ross; López, Victoria; Opie-Martin, Sarah; Vural, Atay; Campos, Yolanda; Weber, Markus; Smith, Bradley; Fogh, Isabella; Silani, Vincenzo; Morrison, Karen E; Dobson, Richard; van Es, Michael A; McLaughlin, Russell L; Vourc'h, Patrick; Chio, Adriano; Corcia, Philippe; de Carvalho, Mamede; Gotkine, Marc; Panades, Monica Povedano; Mora, Jesus S; Shaw, Pamela J; Landers, John E; Glass, Jonathan D; Shaw, Christopher E; Basak, Nazli; Hardiman, Orla; Robberecht, Wim; Van Damme, Philip; van den Berg, Leonard H; Veldink, Jan H; Al-Chalabi, Ammar |
| Contributors: |
Neurology |
| Source: |
Frontiers in cellular neuroscience ; 16 ; 1050596 ; United Kingdom ; United States ; Switzerland |
| Publication Year: |
2023 |
| Collection: |
University of Massachusetts, Medical School: eScholarship@UMMS |
| Subject Terms: |
MND–motor neuron disorders; amyotrophic lateral sclerosis (ALS); bigdata; genomics; telomere–genetics; whole genome sequence (WGS) |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
36589292 |
| Relation: |
Frontiers in Cellular Neuroscience; https://doi.org/10.3389/fncel.2022.1050596; http://hdl.handle.net/20.500.14038/52107 |
| DOI: |
10.3389/fncel.2022.1050596 |
| Availability: |
https://doi.org/10.3389/fncel.2022.1050596; https://hdl.handle.net/20.500.14038/52107 |
| Rights: |
© 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. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. ; Attribution 4.0 International ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.6B8A7E10 |
| Database: |
BASE |