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

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.
Competing Interests: AA-C was a consultant for Mitsubishi-Tanabe Pharma, GSK, and Chronos Therapeutics, and chief investigator for clinical trials for Cytokinetics and OrionPharma. JvV reports to have sponsored research agreements with Biogen. VS was a consultant for Novartis and Biogen. LB reports grants from Netherlands ALS Foundation, grants from Netherlands Organization for Health Research and Development (Vici Scheme), grants from The European Community’s Health Seventh Framework Programme [grant agreement no. 259867 (EuroMOTOR)], grants from Netherlands Organization for Health Research and Development) the STRENGTH project, funded through the EU Joint Programme—Neurodegenerative Disease Research, JPND), during the conduct of the study; personal fees from Calico, personal fees from Cytokinetics, grants and personal fees from Takeda, non-financial support from Orion, non-financial support from Orphazyme, outside the submitted work. AA-C also serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Denali Pharma, Cytokinetics, Lilly, and Amylyx research. CS reports grants from Avexis, grants from Eli Lilly, grants from Chronos Therapeutics, grants from Vertex Pharmaceuticals, during the conduct of the study; grants from QurAlis, grants from Chronos Therapeutics, grants from Biogen, outside the submitted work. JL was a member of the scientific advisory board for Cerevel Therapeutics, a consultant for ACI Clinical LLC sponsored by Biogen, Inc. or Ionis Pharmaceuticals, Inc. JL was also a consultant for Perkins Coie LLP and may provide expert testimony and also supported by funding from NIH/NINDS (R01NS073873 and R56NS073873). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 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.)