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oai:repisalud.isciii.es:20.500.12105/159102025-05-27T12:43:10Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19617
Repisalud author Al Khleifat, Ahmad author Iacoangeli, Alfredo author Jones, Ashley R author van Vugt, Joke J F A author Moisse, Matthieu author Shatunov, Aleksey author Zwamborn, Ramona A J author van der Spek, Rick A A author Cooper-Knock, Johnathan author Topp, Simon author van Rheenen, Wouter author Kenna, Brendan author Van Eijk, Kristel R author Kenna, Kevin author Byrne, Ross author López-Alonso, Victoria author Opie-Martin, Sarah author Vural, Atay author Campos, Yolanda author Weber, Markus author Smith, Bradley author Fogh, Isabella author Silani, Vincenzo author Morrison, Karen E author Dobson, Richard author van Es, Michael A author McLaughlin, Russell L author Vourc'h, Patrick author Chio, Adriano author Corcia, Philippe author de Carvalho, Mamede author Gotkine, Marc author Povedano Panades, Monica author Mora, Jesus S author Shaw, Pamela J author Landers, John E author Glass, Jonathan D author Shaw, Christopher E author Basak, Nazli author Hardiman, Orla author Robberecht, Wim author Van Damme, Philip author van den Berg, Leonard H author Veldink, Jan H author Al-Chalabi, Ammar funder Amyotrophic Lateral Sclerosis Association (Estados Unidos) funder Motor Neurone Disease Association funder Darby Rimmer Foundation funder NIHR - Maudsley Biomedical Research Centre (Reino Unido) funder Wellcome Trust funder Unión Europea. EU Joint Programme-Neurodegenerative Disease Research funder Medical Research Council (Reino Unido) funder Economic and Social Research Council (Reino Unido) funder South London and Maudsley NHS Foundation Trust (Reino Unido) funder Unión Europea. Comisión Europea. 7 Programa Marco funder Unión Europea. Comisión Europea. H2020 funder Unión Europea. Fondo Social Europeo (ESF/FSE) funder King College London funder Science Foundation Ireland funder Research Foundation - Flanders funder Katholieke Universiteit Leuven (Bélgica) 2023-04-27T09:40:45Z 2023-04-27T09:40:45Z 2022-12 Front Cell Neurosci. 2022 Dec 15;16:1050596. 1662-5102 http://hdl.handle.net/20.500.12105/15910 36589292 10.3389/fncel.2022.1050596 Frontiers in cellular neuroscience 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. eng MND-motor neuron disorders Amyotrophic lateral sclerosis (ALS) Bigdata Genomics Telomere-genetics Whole genome sequence (WGS) Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data research article 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 URL https://repisalud.isciii.es/bitstreams/0115fa51-170a-4b55-96f6-756c6950b138/download File MD5 9f5e024504cec6c9357e1c7ba626cd50 897326 application/pdf TelomereLengthAnalysisAmyotrophic_2022.pdf URL https://repisalud.isciii.es/bitstreams/d95f8bc8-043c-4bcb-a634-91b47f7d1193/download File MD5 ed12728c3fef937d6c81088309883b90 163147 application/pdf Supplementary_TelomereLengthAnalysisAmyotrophic_2022.pdf URL https://repisalud.isciii.es/bitstreams/914293fe-1116-42e9-b703-024b190eeb34/download File MD5 d6a48b01352e8262392edfe7acb188cb 49948 text/plain TelomereLengthAnalysisAmyotrophic_2022.pdf.txt URL https://repisalud.isciii.es/bitstreams/f9022a51-42b4-40c8-991a-3008eef2b4eb/download File MD5 9ee4ebf6c094c7f4d46df536f8942020 4433 text/plain Supplementary_TelomereLengthAnalysisAmyotrophic_2022.pdf.txt