TY - JOUR
T1 - Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data
AU - the Project MinE Consortium
AU - Al Khleifat, Ahmad
AU - Iacoangeli, Alfredo
AU - Jones, Ashley R.
AU - van Vugt, Joke J.F.A.
AU - Moisse, Matthieu
AU - Shatunov, Aleksey
AU - Zwamborn, Ramona A.J.
AU - van der Spek, Rick A.A.
AU - Cooper-Knock, Johnathan
AU - Topp, Simon
AU - van Rheenen, Wouter
AU - Kenna, Brendan
AU - Van Eijk, Kristel R.
AU - Kenna, Kevin
AU - Byrne, Ross
AU - López, Victoria
AU - Opie-Martin, Sarah
AU - Vural, Atay
AU - Campos, Yolanda
AU - Weber, Markus
AU - Smith, Bradley
AU - Fogh, Isabella
AU - Silani, Vincenzo
AU - Morrison, Karen E.
AU - Dobson, Richard
AU - van Es, Michael A.
AU - McLaughlin, Russell L.
AU - Vourc’h, Patrick
AU - Chio, Adriano
AU - Corcia, Philippe
AU - de Carvalho, Mamede
AU - Gotkine, Marc
AU - Panades, Monica Povedano
AU - Mora, Jesus S.
AU - Shaw, Pamela J.
AU - Landers, John E.
AU - Glass, Jonathan D.
AU - Shaw, Christopher E.
AU - Basak, Nazli
AU - Hardiman, Orla
AU - Robberecht, Wim
AU - Van Damme, Philip
AU - van den Berg, Leonard H.
AU - Veldink, Jan H.
AU - Al-Chalabi, Ammar
N1 - Publisher Copyright:
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.
PY - 2022/12/15
Y1 - 2022/12/15
N2 - 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.
AB - 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.
KW - amyotrophic lateral sclerosis (ALS)
KW - bigdata
KW - genomics
KW - MND–motor neuron disorders
KW - telomere–genetics
KW - whole genome sequence (WGS)
UR - http://www.scopus.com/inward/record.url?scp=85145322797&partnerID=8YFLogxK
U2 - 10.3389/fncel.2022.1050596
DO - 10.3389/fncel.2022.1050596
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AN - SCOPUS:85145322797
SN - 1662-5102
VL - 16
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
M1 - 1050596
ER -