Frontiers in Cellular Neuroscience (Dec 2022)

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

  • Ahmad Al Khleifat,
  • Alfredo Iacoangeli,
  • Alfredo Iacoangeli,
  • Ashley R. Jones,
  • Joke J. F. A. van Vugt,
  • Matthieu Moisse,
  • Matthieu Moisse,
  • Aleksey Shatunov,
  • Aleksey Shatunov,
  • Ramona A. J. Zwamborn,
  • Rick A. A. van der Spek,
  • Johnathan Cooper-Knock,
  • Simon Topp,
  • Wouter van Rheenen,
  • Brendan Kenna,
  • Kristel R. Van Eijk,
  • Kevin Kenna,
  • Ross Byrne,
  • Victoria López,
  • Sarah Opie-Martin,
  • Atay Vural,
  • Yolanda Campos,
  • Markus Weber,
  • Markus Weber,
  • Bradley Smith,
  • Isabella Fogh,
  • Vincenzo Silani,
  • Vincenzo Silani,
  • Karen E. Morrison,
  • Richard Dobson,
  • Richard Dobson,
  • Michael A. van Es,
  • Russell L. McLaughlin,
  • Patrick Vourc’h,
  • Adriano Chio,
  • Adriano Chio,
  • Philippe Corcia,
  • Philippe Corcia,
  • Mamede de Carvalho,
  • Marc Gotkine,
  • Monica Povedano Panades,
  • Jesus S. Mora,
  • Pamela J. Shaw,
  • John E. Landers,
  • Jonathan D. Glass,
  • Christopher E. Shaw,
  • Christopher E. Shaw,
  • Nazli Basak,
  • Orla Hardiman,
  • Orla Hardiman,
  • Wim Robberecht,
  • Wim Robberecht,
  • Philip Van Damme,
  • Philip Van Damme,
  • Leonard H. van den Berg,
  • Jan H. Veldink,
  • Ammar Al-Chalabi,
  • Ammar Al-Chalabi

DOI
https://doi.org/10.3389/fncel.2022.1050596
Journal volume & issue
Vol. 16

Abstract

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BackgroundAmyotrophic 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.MethodsSamples 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.ResultsThere 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).DiscussionAlthough telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.

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