Telomere length is greater in ALS than in controls: a whole genome sequencing study

Khleifat, Ahmad Al; Iacoangeli, Alfredo; Shatunov, Aleksey; Fang, Ton; Sproviero, William; Jones, Ashley; Opie-Martin, Sarah; Morrison, Karen E.; Shaw, Pamela J.; Powell, John; Dobson, Richard; Newhouse, Stephen; Al‐Chalabi, Ammar

doi:10.1080/21678421.2019.1586951

Cited by 22 publications

(19 citation statements)

References 39 publications

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“…In line with this, accelerated telomere shortening was observed in leukocytes from sporadic PALS (De Felice et al, 2014) and in ALS mice (Linkus et al, 2016). In contrast, in the recent study (Al Khleifat et al, 2019), ALS was associated with the longer telomeres. On the other hand, in the same study, the longer telomeres in patients correlated with increased survival, which would suggest that longer telomeres played a protective role.…”

Section: Telomeresmentioning

confidence: 64%

Potential Preventive Strategies for Amyotrophic Lateral Sclerosis

Kuraszkiewicz

Goszczyńska

Podsiadły-Marczykowska

et al. 2020

Front. Neurosci.

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It may seem useless to propose preventive measures for a disease without established pathogenesis and successful therapy, such as amyotrophic lateral sclerosis (ALS). However, we will show that ALS shares essential molecular mechanisms with aging and that established anti-aging strategies, such as healthy diet or individually adjusted exercise, may be successfully applied to ameliorate the condition of ALS patients. These strategies might be applied for prevention if persons at ALS risk could be identified early enough. Recent research advances indicate that this may happen soon.

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Section: Telomeresmentioning

confidence: 64%

Potential Preventive Strategies for Amyotrophic Lateral Sclerosis

Kuraszkiewicz

Goszczyńska

Podsiadły-Marczykowska

et al. 2020

Front. Neurosci.

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“…Our results are not fully consistent with those in previous studies (Table 1). For example, previous studies displayed distinct association in direction and magnitude between LTL and ALS in the European population 9,14 . Compared to those prior work, our study has the advantage of larger sample size (20,806/59,804 vs. 6,100/7,125 and 1,241/335) and thus holds higher power.…”

Section: Discussionmentioning

confidence: 89%

“…Previous studies proposed that telomerase inhibition could be a pathogenetic contributor to the neurodegeneration in ALS 13 . A recent study 14 , along with ALS animal models 15 , offered some evidence that shorter LTL likely decreased the risk of ALS (Table 1 ). However, it remains uncertain whether such association is causal or not.…”

Section: Introductionmentioning

confidence: 99%

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Gao¹,

Wang²,

Yu³

et al. 2020

Sci Rep

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We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genomewide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population. Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal multisystem neurodegenerative disease, leading to substantial public health threat although it is relatively rare worldwide. However, the cause and pathogenesis underlying ALS mostly remains unknown, with few replicable and definitive risk factors and scarce drugs available 1-4. The number of ALS cases is predicted to increase dramatically due to population aging in the coming years 5 , which would further aggravate the ALS-associated social and economic burden. Therefore, the identification of its risk factors can provide better understanding of ALS and has the potential to pave the way for therapeutic intervention. In the past few years the role of telomere in various complex diseases has attracted much attention 6. Progressive telomere shortening occurs in all dividing normal cells due to incomplete synthesis of DNA lagging-strand, oxidative damage and other factors, which ultimately leads to cellular growth arrest or apoptosis that is thought to be an initial proliferative barrier to tumor development in humans 7. Indeed, recent studies suggested that leukocyte telomere length (LTL) was widely relevant to age-related diseases and disorders (e.g. many types of cancer and coronary heart disease) 8-11. In particular, it was demonstrated that shorter LTL was associated with various neurodegenerative disorders. For example, a latest study showed LTL at baseline and 18 months was shorter in patients of Parkinson's disease (PD) compared to healthy controls 12 , although prior studies found nonsignificant association between LTL and PD (Table 1). In addition, telomere shortening was recognized as an indicator of progression for Alzheimer's disease (AD) (Table 1). However, the knowledge about the relationship between LTL and ALS is very limited. Previous studies proposed th...

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“…The genetics of ALS has proven challenging, and even though great progress has been made by generating and analysing large multi-omics datasets [36,[62][63][64][65][66][67][68][69][70][71], the causes of ALS in most patients (~85%) remain unexplained. Using machine learning models to leverage our current knowledge of ALS and other diseases could allow us to accelerate our progress in the understanding of the genetic causes of ALS and lead towards new avenues of treatment.…”

Section: Discussionmentioning

confidence: 99%

A Knowledge-Based Machine Learning Approach to Gene Prioritisation in Amyotrophic Lateral Sclerosis

Bean

Al‐Chalabi

Dobson

et al. 2020

Genes

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Amyotrophic lateral sclerosis is a neurodegenerative disease of the upper and lower motor neurons resulting in death from neuromuscular respiratory failure, typically within two to five years of first symptoms. Several rare disruptive gene variants have been associated with ALS and are responsible for about 15% of all cases. Although our knowledge of the genetic landscape of this disease is improving, it remains limited. Machine learning models trained on the available protein–protein interaction and phenotype-genotype association data can use our current knowledge of the disease genetics for the prediction of novel candidate genes. Here, we describe a knowledge-based machine learning method for this purpose. We trained our model on protein–protein interaction data from IntAct, gene function annotation from Gene Ontology, and known disease-gene associations from DisGeNet. Using several sets of known ALS genes from public databases and a manual review as input, we generated a list of new candidate genes for each input set. We investigated the relevance of the predicted genes in ALS by using the available summary statistics from the largest ALS genome-wide association study and by performing functional and phenotype enrichment analysis. The predicted sets were enriched for genes associated with other neurodegenerative diseases known to overlap with ALS genetically and phenotypically, as well as for biological processes associated with the disease. Moreover, using ALS genes from ClinVar and our manual review as input, the predicted sets were enriched for ALS-associated genes (ClinVar p = 0.038 and manual review p = 0.060) when used for gene prioritisation in a genome-wide association study.

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Telomere length is greater in ALS than in controls: a whole genome sequencing study

Cited by 22 publications

References 39 publications

Potential Preventive Strategies for Amyotrophic Lateral Sclerosis

Potential Preventive Strategies for Amyotrophic Lateral Sclerosis

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

A Knowledge-Based Machine Learning Approach to Gene Prioritisation in Amyotrophic Lateral Sclerosis

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