Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy

Rodríguez‐Fernández, Blanca; Gispert, Juan Domingo; Guigó, Roderic; Navarro, Arcadi; Vilor‐Tejedor, Natàlia; Crous‐Bou, Marta

doi:10.1016/j.csbj.2022.08.006

Cited by 12 publications

(13 citation statements)

References 52 publications

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“…TL is a well‐known biological marker of aging, 46 and telomeres shorten in age‐related diseases 47,48 . TL has been extensively studied in relation to neurodegenerative diseases, particularly Alzheimer's disease 49,50 . Furthermore, TL has been found to be associated with brain structure, as studies have shown positive correlations between TL and cortical thickness, 51 hippocampal volume, 52 total brain volume, and specific cortical subsegments 53 .…”

Section: Discussionmentioning

confidence: 99%

“…TL is closely associated with biological aging 9,10 and is linked to several diseases and mortality 11,12 . TL varies across different tissues, commonly measured in white blood cells, 10 and has been associated with neurodegenerative diseases 13,14 . Animal studies have demonstrated a negative correlation between TL and seizures, 15 and observational studies have shown telomere shortening in patients with drug‐resistant epilepsy 16 .…”

Section: Introductionmentioning

confidence: 99%

“…11,12 TL varies across different tissues, commonly measured in white blood cells, 10 and has been associated with neurodegenerative diseases. 13,14 Animal studies have demonstrated a negative correlation between TL and seizures, 15 and observational studies have shown telomere shortening in patients with drug-resistant epilepsy. 16 However, traditional statistical methods have limitations in establishing causal relationships, as potential confounders and reverse causality cannot be completely ruled out.…”

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confidence: 99%

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Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study

Luo,

Ruan,

Liu

2023

Epilepsia Open

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ObjectiveObservational studies have suggested a link between telomere length (TL) and epilepsy, but the direction of the effect and whether it is causal or not is still being debated. The objective of this study was to investigate the causal relationship between TL and epilepsy using Mendelian randomization (MR) analysis.MethodsWe performed a bidirectional two‐sample MR analysis using pooled statistics from genome‐wide association studies (GWAS) of TL and epilepsy. Additionally, we conducted a replication analysis using data from another GWAS study on epilepsy to validate our findings. The final results were analyzed using five MR methods, with the inverse‐variance weighted (IVW) method as the primary outcome. We applied methods such as radial MR, MR pleiotropy residual and outlier test and MR Steiger filters to exclude outliers. Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy.ResultsOur analysis found no evidence of a causal relationship between epilepsy and TL (all P‐values > 0.05). The sensitivity analysis confirms the robustness of these results.SignificanceIn summary, our study contradicts existing observational reports by not finding any evidence to support a causal relationship between epilepsy and TL. Further research is necessary to determine the underlying mechanism behind the association observed in observational studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study

Luo,

Ruan,

Liu

2023

Epilepsia Open

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“…For example, a comprehensive MR analysis by The Telomeres Mendelian Randomization Collaboration (2017) showed the strongest positive association between genetically predicted longer TL and a variety of cancers. There were also many MR studies reporting the relationship between TL and neurological diseases, including amyotrophic lateral sclerosis ( Xia et al, 2021 ), Alzheimer’s disease ( Gao et al, 2019 ; Rodriguez-Fernandez et al, 2022 ; Yu et al, 2021 ), multiple sclerosis ( Liao et al, 2022 ; Shu, Li & Zhu, 2022 ). But there are also some MR studies showing that telomere length is not associated with some neurological traits, such as depression ( Wium-Andersen et al, 2017 ), and Parkinson’s disease ( Chen & Zhan, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Leukocyte telomere length and bipolar disorder risk: evidence from Mendelian randomization analysis

Zeng

Wan

et al. 2023

PeerJ

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Objective We aim to test whether leukocyte telomere length (LTL) is causally associated with the risk of bipolar disorder (BD) using the Mendelian randomization (MR) method. Methods Results of a genome-wide association study (GWAS) conducted with 472,174 individuals of European descent were used to screen for single-nucleotide polymorphisms (SNPs) related with LTL traits. Summary-level data for BD (7,647 cases and 27,303 controls) were obtained from UK Biobank. An inverse-variance-weighted (IVW) method was employed as the primary MR analysis. Sensitivity analyses were conducted via MR-Egger, maximum likelihood, MR-pleiotropy residual sum outlier (MR-PRESSO), and MR-robust adjusted profile score (MR-RAPS) methods. Finally, the MR Steiger test was utilized to validate the hypothesized relationship between exposure and outcome. Results Two-sample MR analysis revealed inverse relationships between genetically predicted LTL and BD risk (IVW OR [odds ratio] = 0.800, 95% CI [0.647–0.989] P = 0.039). Genetically predicted LTL exhibits a consistent connection with BD across five MR methods. Sensitivity analyses showed that the genetically determined effect of LTL on BD was stable and reliable. Furthermore, the MR Steiger test demonstrated that LTL was causal for BD rather than the opposite (P < 0.001). Conclusion Our findings show that genetically determined LTL reduces the risk of BD. More research is required to clarify the mechanisms underlying this apparent causal connection. In addition, these findings may be useful for developing strategies for the prevention and treatment of BD.

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“…A study from Adelaide, Australia reported shorter TL in buccal and white blood cells in clinically diagnosed Alzheimer’s patients relative to healthy age-matched controls 26 . Recently, a two-sample Mendelian randomization study leveraging on summary statistics data extracted from largescale GWAS inferred that longer leucocyte TL have a protective effect on risk of Alzheimer’s disease 27 . Nonetheless, one large prospective study comprising n = 1,961 Dutch participants reported an U-shaped association, with higher risks of Alzheimer’s disease in the lowest and highest tertiles of TL relative to the middle tertile 28 .…”

Section: Introductionmentioning

confidence: 99%

The associations of socioeconomic status with incident dementia and Alzheimer’s disease are modified by leucocyte telomere length: a population-based cohort study

Lai

Webster

Kumari

et al. 2023

Sci Rep

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Socio-economic status (SES) and biological aging are risk factors for dementia, including Alzheimer’s disease, however, it is less clear if the associations with SES vary sufficiently across different biological age strata. We used data from 331,066 UK Biobank participants aged 38–73 with mean follow-up of 12 years to examine if associations between SES (assessed by educational attainment, employment status and household income) and dementia and Alzheimer’s disease are modified by biological age (assessed by leucocyte telomere length: LTL). Diagnosis of events was ascertained through hospital admissions data. Cox regressions were used to estimate hazard ratios [HRs]. A consistent dose–response relationship was found, with participants in low SES and shorter LTL strata (double-exposed group) reporting 3.28 (95% confidence interval [CI] 2.57–4.20) and 3.44 (95% CI 2.35–5.04) times higher risks of incident dementia and Alzheimer’s disease respectively, compared to those of high SES and longer LTL (least-exposed group). Of interest is a synergistic interaction between SES and LTL to increase risk of dementia (RERI 0.57, 95% CI 0.07–1.06) and Alzheimer’s disease (RERI 0.79, 95% CI 0.02–1.56). Our findings that SES and biological age (LTL) are synergistic risk factors of dementia and Alzheimer’s disease may suggest the need to target interventions among vulnerable sub-groups.

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Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy

Cited by 12 publications

References 52 publications

Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study

Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study

Leukocyte telomere length and bipolar disorder risk: evidence from Mendelian randomization analysis

The associations of socioeconomic status with incident dementia and Alzheimer’s disease are modified by leucocyte telomere length: a population-based cohort study

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