scholarly journals Assessing the Causal Role of Selenium in Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Di He ◽  
Liying Cui
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mendelian Randomization ◽  
Epidemiologic Studies ◽  
European Population ◽  
Causal Role ◽  
Sensitivity Analyses ◽  
Current Evidence ◽  
Inverse Variance ◽  
Lateral Sclerosis

Objectives: The relation between selenium overexposure and increased risk of amyotrophic lateral sclerosis (ALS) has been subject to considerable interest. Epidemiologic studies have reported suggestive associations between selenium and ALS, although the causal inference between selenium and ALS remains to be established.Methods: We conducted a two-sample Mendelian randomization (MR) analysis to analyze the causal role of selenium on ALS risk. Variants associated with selenium levels were obtained from the GWAS meta-analysis of circulating selenium levels (n = 5,477) and toenail selenium levels (n = 4,162) in the European population. Outcome data were from the largest ALS GWAS dataset with 20,806 ALS cases and 59,804 controls in the European population. Inverse variance weighted (IVW) method was used as the main analysis, with an array of sensitivity analyses performed to detect potential violations of MR assumptions.Results: Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in ALS development (odds ratio (OR) = 1.02, 95% confidence interval (CI) = 0.96–1.08). Similar results were observed for the sensitivity analyses (OR = 1.00, 95% CI = 0.95–1.07 for weighted median; OR = 1.07, 95% CI = 0.87–1.32 for MR-Egger), with no pleiotropy detected.Conclusions: Although selenium was found associated with ALS according to earlier epidemiologic studies, current evidence based on the population of European ancestry does not support the causal effect of selenium on ALS risk.

scholarly journals Assessing the Causal Role of Selenium in Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Di He ◽  
Liying Cui
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mendelian Randomization ◽  
Epidemiologic Studies ◽  
Causal Role ◽  
Sensitivity Analyses ◽  
Current Evidence ◽  
Inverse Variance ◽  
Increased Risk ◽  
Lateral Sclerosis

Abstract Background: The relation between selenium overexposure and increased risk of amyotrophic lateral sclerosis (ALS) has been subject to considerable interest. Epidemiologic studies have reported suggestive associations between selenium and ALS, although the causal inference between selenium and ALS remains to be established. Here we conducted a two-sample Mendelian randomization (MR) analysis to analyze the causal role of selenium on ALS risk.Methods: Variants associated with selenium levels were obtained from the GWAS meta-analysis of circulating selenium levels (n = 5,477) and toenail selenium levels (n = 4,162). Outcome data were from the largest ALS GWAS dataset with 20,806 ALS cases and 59,804 controls. Inverse variance weighted (IVW) method was used as the main analysis, with an array of sensitivity analyses performed to detect potential violations of MR assumptions.Results: Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in ALS development (odds ratio [OR] = 1.02, 95% confidence interval [CI] = 0.96–1.08). Similar results were observed for sensitivity analyses (OR = 1.00, 95% CI 0.95–1.07 for weighted median; OR = 1.07, 95% CI = 0.87–1.32 for MR-Egger), with no pleiotropy detected.Conclusion: Although selenium was found associated with ALS according to earlier epidemiologic studies, current evidence does not support the causal effect of selenium on ALS risk. Correcting overall selenium levels in general population will unlikely reduce ALS incidence.

scholarly journals Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study

2021 ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Lu Tang ◽  
Tao Huang ◽  
Dongsheng Fan
Keyword(s):  
Blood Pressure ◽  
Amyotrophic Lateral Sclerosis ◽  
Protective Factor ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inverse Variance ◽  
High Level ◽  
Lateral Sclerosis

Abstract Background Observational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to investigate whether there is a causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertension drugs (AHDs), ALS, and their corresponding genome-wide association studies (GWAS) summary datasets were obtained from the updated largest studies. Inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods for sensitivity analyses. To exclude the interference between SBP and DBP, multivariable MR was used. Results We found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960–0.996, P = 0.017), and increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003–1.025, P = 0.015). The high level of targeted protein of Calcium channel blocker (CCB) showed a causative relationship with ALS (OR = 0.985, 95% CI 0.971-1.000, P = 0.049). No evidence was revealed that ALS caused results change of BP measurements. Conclusions This study demonstrated that an increase in DBP is a protective factor for ALS, and increased SBP is independently risk for ALS, which may be related to sympathetic excitability. Blood pressure management is important in ALS, in which CCB may be a promising candidate.

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.

scholarly journals Genetically Predicted Circulating Concentrations of Micronutrients and Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Changqing Mu ◽  
Yating Zhao ◽  
Chen Han ◽  
Dandan Tian ◽  
Na Guo ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Inverse Variance ◽  
Effective Role ◽  
Copper Zinc ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.

scholarly journals Iron Status May Not Affect Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahao Cai ◽  
Xiong Chen ◽  
Hongxuan Wang ◽  
Zixin Wei ◽  
Mei Li ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Outcome Data ◽  
Sensitivity Analyses ◽  
A Genome ◽  
Lateral Sclerosis

BackgroundObservational studies have shown an association of increased iron status with a higher risk of amyotrophic lateral sclerosis (ALS). Iron status might be a novel target for ALS prevention if a causal relationship exists. We aimed to reveal the causality between iron status and ALS incidence using a large two-sample Mendelian randomization (MR).MethodsSingle nucleotide polymorphisms (SNPs) for iron status were identified from a genome-wide association study (GWAS) on 48,972 individuals. The outcome data came from the largest ALS GWAS to date (20,806 cases; 59,804 controls). We conducted conservative analyses (using SNPs with concordant change of biomarkers of iron status) and liberal analyses (using SNPs associated with at least one of the biomarkers of iron status), with inverse variance weighted (IVW) method as the main analysis. We then performed sensitivity analyses including weighted median, MR-Egger and MR-pleiotropy residual sum and outlier, as well as leave-one-out analysis to detect pleiotropy.ResultsIn the conservative analyses, we found no evidence of association between four biomarkers of iron status and ALS using IVW method with odds ratio (OR) 1.00 [95% confidence interval (CI): 0.90–1.11] per standard deviation (SD) increase in iron, 0.96 (95% CI: 0.77–1.21) in ferritin, 0.99 (95% CI: 0.92–1.07) in transferrin saturation, and 1.04 (95% CI: 0.93–1.16) in transferrin. Findings from liberal analyses were similar, and sensitivity analyses suggested no pleiotropy detected (all p > 0.05).ConclusionOur findings suggest no causal effect between iron status and risk of ALS. Efforts to change the iron status to decrease ALS incidence might be impractical.

scholarly journals Association between premorbid body mass index and amyotrophic lateral sclerosis: causal inference through genetic approaches

2019 ◽  
Author(s):  
Ping Zeng ◽  
Xinghao Yu ◽  
Haibo Xu
Keyword(s):  
Body Mass Index ◽  
Amyotrophic Lateral Sclerosis ◽  
Causal Relationship ◽  
Body Mass ◽  
European Population ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inverse Association ◽  
Standard Deviation Increase ◽  
Lateral Sclerosis

Background: Inverse association between premorbid body mass index (BMI) and amyotrophic lateral sclerosis (ALS) has been discovered in observational studies; however, whether this association is causal remains largely unknown. Methods: We employed a two-sample Mendelian randomization approach to evaluate the causal relationship of genetically increased BMI with the risk of ALS. The analyses were implemented using summary statistics obtained for the independent instruments identified from large-scale genome-wide association studies of BMI (up to ~770,000 individuals) and ALS (up to ~81,000 individuals). The causal relationship between BMI and ALS was estimated using inverse-variance weighted methods and was further validated through extensive complementary and sensitivity analyses. Findings: Using 1,031 instruments strongly related to BMI, the causal effect of per one standard deviation increase of BMI was estimated to be 1.04 (95% CI 0.97~1.11, p=0.275) in the European population. The null association between BMI and ALS discovered in the European population also held in the East Asian population and was robust against various modeling assumptions and outlier biases. Additionally, the Egger-regression and MR-PRESSO ruled out the possibility of horizontal pleiotropic effects of instruments. Interpretation: Our results do not support the causal role of genetically increased or decreased BMI on the risk of ALS.

scholarly journals Causal Effects of Blood Lipids on Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2018 ◽  
Author(s):  
Ping Zeng ◽  
Xiang Zhou
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
East Asian ◽  
Density Lipoprotein ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Asian Populations ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades. Understanding the disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG) on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per one standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 (95% CI 1.05 - 1.24, p = 1.38E-3) in the European and population and 1.06 (95% CI 1.00 - 1.12, p = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations.

scholarly journals Relationship of Soluble Interleukin-6 Receptors With Asthma: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Yoshihiko Raita ◽  
Zhaozhong Zhu ◽  
Carlos A. Camargo ◽  
Robert J. Freishtat ◽  
Debby Ngo ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Study Data ◽  
Sensitivity Analyses ◽  
Receptor Level ◽  
Inverse Variance ◽  
Interleukin 6 Receptor ◽  
The Uk

Purpose: Emerging evidence suggests a potential role of interleukin-6 pathways—trans-signaling with soluble interleukin-6 receptors—in the asthma pathobiology. Despite the evidence for their associations with asthma, the causal role of soluble interleukin-6 receptors remains uncertain. We investigated the relations of soluble interleukin-6 receptors with asthma and its major phenotypes.Methods: We conducted a two-sample Mendelian randomization study. As genetic instruments, we selected 33 independent cis-acting variants strongly associated with the level of plasma soluble interleukin-6 receptor in the INTERVAL study. To investigate the association of variants with asthma and its phenotypes, we used genome-wide association study data from the UK Biobank. We combined variant-specific causal estimates by the inverse-variance weighted method for each outcome.Results: Genetically-instrumented soluble interleukin-6 receptor level was associated with a significantly higher risk of overall asthma (OR per one standard deviation increment in inverse-rank normalized soluble interleukin-6 receptor level, 1.02; 95%CI, 1.01–1.03; P = 0.004). Sensitivity analyses demonstrated consistent results and indicated no directional pleiotropy—e.g., MR-Egger (OR, 1.03; 95%CI, 1.01–1.05; P = 0.002; Pintercept =0.37). In the stratified analysis, the significant association persisted across asthma phenotypes—e.g., childhood asthma (OR, 1.05; 95%CI, 1.02–1.08; P < 0.001) and obese asthma (OR, 1.02; 95%CI 1.01–1.03; P = 0.007). Sensitivity analysis using 16 variants selected with different thresholds also demonstrated significant associations with overall asthma and its phenotypes.Conclusion: Genetically-instrumented soluble interleukin-6 receptor level was causally associated with modestly but significantly higher risks of asthma and its phenotypes. Our observations support further investigations into identifying specific endotypes in which interleukin-6 pathways may play major roles.

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

2021 ◽  
Vol 16 (1) ◽  
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, whether this association is causal remains unclear. In this study, we aimed to explore the causal relationship between leukocyte telomere length (LTL) and ALS by a two-sample Mendelian randomization (MR) approach. Single-nucleotide polymorphisms (SNPs) for LTL were identified through high-quality genome-wide association studies (GWASs). The ALS GWAS summary data (20,806 cases; 59,804 controls) with largest sample size to date was obtained. 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 increased LTL was inversely associated with the risk of ALS (odds ratio (OR) = 0.846, 95% confidence interval (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. The results were further confirmed by sensitivity analysis with the MR Egger method (OR = 0.647, 95% CI = 0.447–0.936, P = 0.050). Analyses by the weighted median method (OR = 0.893, P = 0.201) and simple median method (OR = 0.935, P = 0.535) also showed a similar trend. The MR Egger analysis did not suggest directional pleiotropy, with 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 increased LTL has a causal relationship with a lower risk of ALS. Protecting against telomere loss may be of great importance in the prevention and treatment of ALS.

scholarly journals Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengyu Li ◽  
Chris Ho Ching Yeung ◽  
C. Mary Schooling
Keyword(s):  
Immune System ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Multiple Comparisons ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inflammatory Protein ◽  
Inverse Variance ◽  
System Functioning

BackgroundImmune system functioning is relevant to vulnerability to coronavirus disease (COVID-19). Cytokines are important to immunity. To further elucidate the role of the immune system in COVID-19, we used Mendelian randomization (MR) to assess comprehensively and bi-directionally the role of cytokines in COVID-19.MethodsWe assessed primarily whether genetically different levels of 41 cytokines affected risk of any COVID-19 (laboratory confirmed, physician confirmed or self-reported, 36,590 cases, 1,668,938 controls), and conversely if genetic risk of liability to any COVID-19 affected these cytokines (n ≤ 8293) using the most recent genome-wide association studies. We obtained inverse variance weighting (IVW) estimates, conducted sensitivity analyses and used a Benjamini-Hochberg correction to account for multiple comparisons. We also assessed whether any findings were evident for hospitalized COVID-19 (hospitalized laboratory confirmed, 12,888 cases, 1,295,966 controls).ResultsMacrophage inflammatory protein-1β (MIP1b; more commonly known as Chemokine (C-C motif) ligands 4 (CCL4) was inversely associated with COVID-19 [odds ratio (OR) 0.97 per SD, 95% confidence interval (CI) 0.96–0.99] but not after adjustment for multiple comparisons. This finding replicated for hospitalized COVID-19 (OR 0.93, 95% CI 0.89–0.98). Liability to any COVID-19 was nominally associated with several cytokines, such as granulocyte colony-stimulating factor (GCSF) and hepatocyte growth factor (HGF) but not after correction.ConclusionA crucial element of immune response to infection (CCL4) was related to COVID-19, whether it is a target of intervention to prevent COVID-19 warrants further investigation.

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