scholarly journals No Causal Effect of Telomere Length on Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 159 ◽  
Author(s):  
Weijie Cao ◽  
Xingang Li ◽  
Xiaoyu Zhang ◽  
Jie Zhang ◽  
Qi Sun ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Telomere Length ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Genome Wide Association Studies ◽  
Large Artery ◽  
Genome Wide ◽  
Inverse Variance ◽  
A Genome ◽  
Weighted Median

Background: Epidemiological studies observing inconsistent associations of telomere length (TL) with ischemic stroke (IS) are susceptible to bias according to reverse causation and residual confounding. We aimed to assess the causal association between TL, IS, and the subtypes of IS, including large artery stroke (LAS), small vessel stroke (SVS), and cardioembolic stroke (CES) by performing a series of two-sample Mendelian randomization (MR) approaches. Methods: Seven single nucleotide polymorphisms (SNPs) were involved as candidate instrumental variables (IVs), summarized from a genome-wide meta-analysis including 37,684 participants of European descent. We analyzed the largest ever genome-wide association studies of stroke in Europe from the MEGASTROKE collaboration with 40,585 stroke cases and 406,111 controls. The weighted median (WM), the penalized weighted median (PWM), the inverse variance weighted (IVW), the penalized inverse variance weighted (PIVW), the robust inverse variance weighted (RIVW), and the Mendelian randomization-Egger (MR-Egger) methods were conducted for the MR analysis to estimate a causal effect and detect the directional pleiotropy. Results: No significant association between genetically determined TL with overall IS, LAS, or CES were found (all p > 0.05). SVS was associated with TL by the RIVW method (odds ratio (OR) = 0.72, 95% confidence interval (CI): 0.54–0.97, p = 0.028), after excluding rs9420907, rs10936599, and rs2736100. Conclusions: By a series of causal inference approaches using SNPs as IVs, no strong evidence to support the causal effect of shorter TL on IS and its subtypes were found.

scholarly journals A Mendelian randomization analysis of the relationship between cardioembolic risk factors and ischemic stroke

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Danyang Tian ◽  
Linjing Zhang ◽  
Zhenhuang Zhuang ◽  
Tao Huang ◽  
Dongsheng Fan
Keyword(s):  
Risk Factors ◽  
Ischemic Stroke ◽  
Mendelian Randomization ◽  
P Wave ◽  
Cardioembolic Stroke ◽  
Large Artery ◽  
Weighted Analysis ◽  
Inverse Variance ◽  
Weighted Median ◽  
Genetically Determined

AbstractObservational studies have shown that several risk factors are associated with cardioembolic stroke. However, whether such associations reflect causality remains unknown. We aimed to determine whether established and provisional cardioembolic risk factors are causally associated with cardioembolic stroke. Genetic instruments for atrial fibrillation (AF), myocardial infarction (MI), electrocardiogram (ECG) indices and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were obtained from large genetic consortiums. Summarized data of ischemic stroke and its subtypes were extracted from the MEGASTROKE consortium. Causal estimates were calculated by applying inverse-variance weighted analysis, weighted median analysis, simple median analysis and Mendelian randomization (MR)-Egger regression. Genetically predicted AF was significantly associated with higher odds of ischemic stroke (odds ratio (OR): 1.20, 95% confidence intervals (CI): 1.16–1.24, P = 6.53 × 10–30) and cardioembolic stroke (OR: 1.95, 95% CI: 1.85–2.06, P = 8.81 × 10–125). Suggestive associations were found between genetically determined resting heart rate and higher odds of ischemic stroke (OR: 1.01, 95% CI: 1.00–1.02, P = 0.005), large-artery atherosclerotic stroke (OR: 1.02, 95% CI: 1.00–1.04, P = 0.026) and cardioembolic stroke (OR: 1.02, 95% CI: 1.00–1.04, P = 0.028). There was no causal association of P‐wave terminal force in the precordial lead V1 (PTFVI), P-wave duration (PWD), NT-pro BNP or PR interval with ischemic stroke or any subtype.

Causal association of adipokines with osteoarthritis: a Mendelian randomization study

Rheumatology ◽  
2020 ◽  
Author(s):  
Jiayao Fan ◽  
Jiahao Zhu ◽  
Lingling Sun ◽  
Yasong Li ◽  
Tianle Wang ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Knee Oa ◽  
Genome Wide ◽  
A Genome ◽  
Weighted Median

Abstract Objective This two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA. Methods Summary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results. Results The positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13–5.09] and weighted median (OR: 2.94, 95% CI: 1.23–6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01–1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18–10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03–1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis. Conclusions An association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

scholarly journals Association Between Covid-19 and Heart Failure: Evidence From a Two-sample Mendelian Randomization Study

2021 ◽  
Author(s):  
Huachen Wang ◽  
Zheng Guo ◽  
Yulu Zheng ◽  
Bing Chen
Keyword(s):  
Heart Failure ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Reverse Causality ◽  
Genome Wide ◽  
Weighted Median

Abstract Background: Current research observing inconsistent associations of Corona Virus Disease 2019 (COVID-19) with heart failure (HF) are prone to bias based on reverse causality and residual confounding factors. Our aim was to apply a two-sample Mendelian randomization method to investigate whether COVID-19 has a causal effect on HF. Methods: Twenty-nine single nucleotide polymorphisms (SNPs) were proposed as candidate instrumental variables (IVs). A total of 3,523 patients with COVID-19 and 36,634 control participants were included in the genome-wide meta-analysis. We analyzed the largest genome-wide association studies (GWAS) meta-analysis of heart failure in individuals of European ancestry consisting of 47,309 patients with HF and 930,014 controls. The inverse variance weighted (IVW), the Mendelian randomization-Egger (MR-Egger) regression, the simple mode (SM), weighted median, and weighted mode were utilized for the MR analysis to test the stability and a causal effect. Results: The IVW, MR-Egger regression, SM, weighted median and weighted mode demonstrated there was no association between the genetically predicted COVID-19 infection and HF risk (OR, 1.004; 95%CI, 0.994-1.014; P=0.467; OR, 1.008; 95%CI, 0.996-1.019; P=0.218; OR, 0.968; 95%CI, 0.924-1.015; P=0.186; OR, 1.001; 95%CI, 0.988-1.014; P=0.881; OR, 1.001; 95%CI, 0.989-1.014; P=0.836; respectively). Conclusion: This two-sample Mendelian randomization analysis provided no evidence to sustain the causality of COVID-19 on HF.

scholarly journals Association between genetically predicted telomere length and facial skin aging in the UK Biobank: a Mendelian randomization study

GeroScience ◽  
2020 ◽  
Author(s):  
Yiqiang Zhan ◽  
Sara Hägg
Keyword(s):  
Telomere Length ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Large Population ◽  
Uk Biobank ◽  
Facial Aging ◽  
Genome Wide ◽  
A Genome ◽  
Weighted Median ◽  
The Uk

Abstract Are shorter telomeres causal risk factors for facial aging on a large population level? To examine if longer, genetically predicted telomeres were causally associated with less facial aging using Mendelian randomization analysis. Two-sample Mendelian randomization methods were applied to the summary statistics of a genome-wide association study (GWAS) for self-reported facial aging from 417, 772 participants of the UK Biobank data. Twenty single-nucleotide polymorphisms (SNPs) that were of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and were complemented with the MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. Longer genetically predicted telomeres were associated with a lower likelihood of facial aging (β = − 0.02, 95% confidence interval: − 0.04, − 0.002). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was close to zero (0.002) that was not suggestive of horizontal pleiotropy. Our findings provided evidence to support a potential causal relationship between longer genetically predicted telomeres and less facial aging.

The causal effect of interleukin-17 on the risk of psoriatic arthritis: a Mendelian randomization study

Rheumatology ◽  
2020 ◽  
Author(s):  
Dongze Wu ◽  
Priscilla Wong ◽  
Steven H M Lam ◽  
Edmund K Li ◽  
Ling Qin ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Preliminary Evidence ◽  
Interleukin 17 ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Tnf Α ◽  
Weighted Median

Abstract Objective To determine causal associations between genetically predicted TNF-α, IL-12p70 and IL-17 levels and risk of PsA. Methods The publicly available summary-level findings from genome-wide association studies (GWAS) was used to identify loci influencing normal physiological concentrations of TNF-α, IL-12p70 and IL-17 (n = 8293) among healthy individuals as exposure and a GWAS for PsA from the UK Biobank (PsA = 900, control = 462 033) as the outcome. A two-sample Mendelian randomization (MR) analysis was performed using the inverse-variance weighted (IVW), weighted median and MR–Egger regression methods. Sensitivity analysis and MR–Egger regression analysis were performed to evaluate the heterogeneity and pleiotropic effects of each variant. Results Single-nucleotide polymorphisms (SNPs) at genome-wide significance from GWASs on TNF-α, IL-12p70 and IL-17 were identified as the instrumental variables. The IVW method indicated a causal association between increased IL-17 level and risk of PsA (β = −0.00186 per allele, s.e. = 0.00043, P = 0.002). Results were consistent in the weighted median method (β = −0.00145 per allele, s.e. = 0.00059, P = 0.014) although the MR–Egger method suggested a non-significant association (β = −0.00133 per allele, s.e. = 0.00087; P = 0.087). Single SNP MR results revealed that the C allele of rs117556572 was robustly associated with risk of PsA (β = 0.00210, s.e. = 0.00069, P = 0.002). However, no evidence for a causal effect was observed between TNF-α, IL-12p70, decreased IL-17 levels and risk of PsA. Conclusion Our findings provide preliminary evidence that genetic variants predisposing to higher physiological IL-17 level are associated with decreased risk of PsA.

scholarly journals Genetically Predicted Telomere Length and Its Relationship With Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Guangping Yu ◽  
Leihong Lu ◽  
Zaihong Ma ◽  
Shouhai Wu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Telomere Length ◽  
Genome Wide Association Study ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Inverse Variance ◽  
A Genome ◽  
Summary Effect ◽  
Weighted Median

Are shorter telomeres causal risk factors for Alzheimer’s disease (AD)? This study aimed to examine if shorter telomeres were causally associated with a higher risk of AD using Mendelian randomization (MR) analysis. Two-sample MR methods were applied to the summary effect sizes and standard errors from a genome-wide association study for AD. Twenty single nucleotide polymorphisms of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and complemented with the other three methods: weighted median approaches, MR-Egger regression, and weighted mode approach. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. We found that longer telomeres were associated with lower risks of AD (odds ratio = 0.79, 95% confidence interval: 0.67, 0.93, P = 0.004). Comparable results were obtained using weighted median approaches, MR-Egger regression, and weighted mode approaches. The intercept of the MR-Egger regression was close to zero. This may show that there was not suggestive of horizontal pleiotropy. Our findings provided additional evidence regarding the putative causal association between shorter telomere length and the higher risk of AD.

scholarly journals Causal Relationship Between Parathyroid Hormone and the Risk of Osteoarthritis: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Guiwu Huang ◽  
Yanlin Zhong ◽  
Wenchang Li ◽  
Weiming Liao ◽  
Peihui Wu
Keyword(s):  
Parathyroid Hormone ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Inverse Association ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median

BackgroundPrevious studies have demonstrated an inverse association between parathyroid hormone (PTH) and the risk of osteoarthritis (OA). However, it remains unknown whether such association reflects causality. We aimed to apply a Mendelian randomization (MR) approach to investigate the causal association between PTH and OA.Materials and MethodsWe performed a two-sample MR analysis using summary statistics from 13 cohorts (PTH, N = 29,155) and a recent genome-wide association study meta-analysis (OA, N = 455,221) by the UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). MR analyses were carried out mainly using the inverse-variance-weighted method. Sensitivity analyses were performed to test the robustness of the associations using the weighted median method, the MR–Egger method, and “leave-one-out” analysis. Analyses were performed again to test whether the associations remained statistically significant after excluding any outlier variants that were detected using the MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) test.ResultsFive single-nucleotide polymorphisms (SNPs) were selected as instrumental variables at the genome-wide significance threshold (p < 5 × 10–8). The causal effect between PTH and OA was genetically predicted using the inverse-variance-weighted method (odds ratio = 0.67, 95% confidence interval: 0.50–0.90; p = 0.008). This result was borne out using the weighted median method (odds ratio = 0.73, 95% confidence interval: 0.60–0.90; p = 0.004). The causality remained robust after discarding the outlier variants as well as SNPs associated with confounding factors.ConclusionMR analysis supported a potential causative relationship between decreased serum circulating PTH and a higher risk of hip and knee OA.

EXPRESS: Effect of genetic liability to visceral adiposity on stroke and its subtypes: a Mendelian randomization study

2021 ◽  
pp. 174749302110062
Author(s):  
Bin Yan ◽  
Jian Yang ◽  
Li Qian ◽  
Fengjie Gao ◽  
Ling Bai ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Ischemic Stroke ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Visceral Adiposity ◽  
Large Artery ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
A Genome ◽  
Increased Risk

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5×10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48×10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01×10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16×10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

scholarly journals Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

2021 ◽  
Author(s):  
Shuai Yuan ◽  
Maria Bruzelius ◽  
Susanna C. Larsson
Keyword(s):  
Renal Function ◽  
Venous Thromboembolism ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Increased Risk ◽  
Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

scholarly journals Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study

2021 ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Gan Zhang ◽  
Yajun Wang ◽  
Tao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Telomere Length ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Leukocyte Telomere Length ◽  
Weighted Median ◽  
Lateral Sclerosis

Abstract Background Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. We employed a two-sample Mendelian randomization (MR) approach to explore the causal relationship between leukocyte telomere length (LTL) and ALS based on the most cited and most recent and largest LTL genome-wide association studies (GWASs) that measured LTL with the Southern blot method (n = 9190) and ALS GWAS summary data (n = 80,610). We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR PRESSO method to perform sensitivity analyses. Results We found that genetically determined longer LTL was inversely associated with the risk of ALS (OR = 0.846, 95% CI: 0.744–0.962, P = 0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. In sensitivity analyses, that was confirmed in MR Egger method (OR = 0.647,95% CI = 0.447–0.936, P = 0.050), and a similar trend was shown with the weighted median method (OR = 0.893, P = 0.201) and simple median method (OR = 0.935 P = 0.535). The MR Egger analyses did not suggest directional pleiotropy, showing an intercept of 0.025 (P = 0.168). Neither the influence of instrumental outliers nor heterogeneity was found. Conclusions Our results suggest that genetically predicted longer LTL has a causal relationship with a lower risk of ALS and underscore the importance of protecting against telomere loss in ALS.

Sign in / Sign up

Export Citation Format

Share Document