Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data.
Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data.
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DOI：
10.3389/fncel.2022.1050596
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发表时间：
2022
影响因子：
5.3
通讯作者：
Al-Chalabi, Ammar
中科院分区：
文献类型：
--
作者：
Al Khleifat, Ahmad;Iacoangeli, Alfredo;Jones, Ashley R.;van Vugt, Joke J. F. A.;Moisse, Matthieu;Shatunov, Aleksey;Zwamborn, Ramona A. J.;van der Spek, Rick A. A.;Cooper-Knock, Johnathan;Topp, Simon;van Rheenen, Wouter;Kenna, Brendan;Van Eijk, Kristel R.;Kenna, Kevin;Byrne, Ross;Lopez, Victoria;Opie-Martin, Sarah;Vural, Atay;Campos, Yolanda;Weber, Markus;Smith, Bradley;Fogh, Isabella;Silani, Vincenzo;Morrison, Karen E.;Dobson, Richard;van Es, Michael A.;McLaughlin, Russell L.;Vourc'h, Patrick;Chio, Adriano;Corcia, Philippe;de Carvalho, Mamede;Gotkine, Marc;Panades, Monica Povedano;Mora, Jesus S.;Shaw, Pamela J.;Landers, John E.;Glass, Jonathan D.;Shaw, Christopher E.;Basak, Nazli;Hardiman, Orla;Robberecht, Wim;Van Damme, Philip;van den Berg, Leonard H.;Veldink, Jan H.;Al-Chalabi, Ammar
关键词：
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是上下运动神经元丧失，导致随意肌进行性无力，通常在3至5年内因神经肌肉呼吸衰竭而死亡。基因对ALS的风险有很大的影响。在10%或更多的家庭中，有ALS或额颞叶痴呆的家族史，并且在这些家庭中，大约50%的病例中已经确定了导致ALS的孟德尔基因。只有大约14%的明显散发的ALS是由已知的遗传变异来解释的，这表明其他形式的遗传变异很重要。端粒在细胞复制过程中维持DNA的完整性，因性别而异，并随年龄自然缩短。性别和年龄是ALS的危险因素，因此我们研究了ALS的端粒长度。样本来自Project MinE，一个国际ALS全基因组测序联盟，包括表型数据。为了验证，我们使用了ALS患者和对照组捐献的运动皮层大脑样本。通过DNA微阵列数据的主成分分析和关系矩阵来评估祖先和亲缘关系。全基因组序列数据来自Illumina HiSeq平台，并使用Isaac管道进行比对。TelSeq使用全基因组序列数据定量端粒长度。我们使用Cox回归测试了端粒长度与ALS和ALS生存的关系。共有6580个全基因组序列，经过质量控制后减少到6195个样本（4315个来自ALS患者和1880个对照组），159个大脑样本（106个ALS， 53个对照组）。考虑到年龄和性别，与对照组相比，ALS患者端粒长度增加了20% (95% CI 14%, 25%) (p = 1.1 × 10 - 12)，在大脑样本中得到验证（p = 0.03）。端粒较短的患者中位生存期增加10% （p = 5.0×10−7）。虽然散发性ALS和家族性ALS的端粒长度没有差异（p=0.64），但334例由于C9orf72重复扩增的ALS患者的端粒长度比没有C9orf72重复扩增的ALS患者短（p= 5.0×10−4）。虽然端粒随着年龄的增长而缩短，但端粒变长是ALS的危险因素，而且会导致预后恶化。较长的端粒与渐冻症有关。
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. 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. 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). Although 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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影响因子：
9.9
作者：
Crockford C;Newton J;Lonergan K;Chiwera T;Booth T;Chandran S;Colville S;Heverin M;Mays I;Pal S;Pender N;Pinto-Grau M;Radakovic R;Shaw CE;Stephenson L;Swingler R;Vajda A;Al-Chalabi A;Hardiman O;Abrahams S
通讯作者：
Abrahams S
影响因子：
11.4
作者：
BRYAN, TM;ENGLEZOU, A;REDDEL, RR
通讯作者：
REDDEL, RR
DOI：
10.1016/s1474-4422(14)70219-4
发表时间：
2014-11
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Al-Chalabi A;Calvo A;Chio A;Colville S;Ellis CM;Hardiman O;Heverin M;Howard RS;Huisman MHB;Keren N;Leigh PN;Mazzini L;Mora G;Orrell RW;Rooney J;Scott KM;Scotton WJ;Seelen M;Shaw CE;Sidle KS;Swingler R;Tsuda M;Veldink JH;Visser AE;van den Berg LH;Pearce N
通讯作者：
Pearce N
影响因子：
14.9
作者：
Ding Z;Mangino M;Aviv A;Spector T;Durbin R;UK10K Consortium
通讯作者：
UK10K Consortium
影响因子：
168.9
作者：
Hakin-Smith, V;Jellinek, DA;Royds, JA
通讯作者：
Royds, JA