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

• DOI: 10.3389/fncel.2022.1050596
• Publication Date: 2022-12-15T08:02:34Z
• Authors: Ahmad Al Khleifat; Alfredo Iacoangeli; Ashley R. Jones; Joke J. F. A. van...; Matthieu Moisse; Aleksey Shatunov; Ramona A. J. Zwam...; Rick A. A. van de...; Johnathan Cooper-...; 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; Bradley Smith; Isabella Fogh; Vincenzo Silani; Karen E. Morrison; Richard Dobson; Michael A. van Es; Russell L. McLaug...; Patrick Vourc’h; Adriano Chio; Philippe Corcia; Mamede de Carvalho; Marc Gotkine; Monica Povedano P...; Jesus S. Mora; Pamela J. Shaw; John E. Landers; Jonathan D. Glass; Christopher E. Shaw; Nazli Basak; Orla Hardiman; Wim Robberecht; Philip Van Damme; Leonard H. van de...; Jan H. Veldink; Ammar Al-Chalabi
• Keywords: Sequence (biology)

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