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 High Level of Uromodulin Increases the Risk of Hypertension: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Ruilian You ◽  
Lanlan Chen ◽  
Lubin Xu ◽  
Dingding Zhang ◽  
Haitao Li ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Inverse Variance ◽  
The Uk ◽  
High Level

Background: The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure.Methods: We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis.Results: MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.04 (95% Confidence Interval (CI), 1.03-1.04, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 2.70E-04) in “ieu-b-38” and “ukb-b-20175”, respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, P = 4.38E-06) in “ieu-b-39” and 0.05 (SE = 0.01, P = 2.13E-10) in “ukb-b-7992”. As for the sUMOD, the OR of hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.01 (95% CI 1.01–1.02, all P < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in “ieu-b-38” and 0.01 (SE = 0.003, P = 1.04E-04) in “ukb-b-20175”. The sUMOD is causally associated with elevated DBP (“ieu-b-39”: β = 0.313, SE = 0.050, P = 3.43E-10; “ukb-b-7992”: β = 0.018, SE = 0.003, P = 8.41E-09).Conclusion: Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.

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 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 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. 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. 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.

Timing of pubertal development and midlife blood pressure in men and women: A Mendelian randomization study

2021 ◽  
Author(s):  
Io Ieong Chan ◽  
Man Ki Kwok ◽  
C Mary Schooling
Keyword(s):  
Blood Pressure ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Pubertal Development ◽  
Sensitivity Analyses ◽  
Age At Menarche ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Pubertal Maturation ◽  
Pubertal Growth

Abstract Introduction Observational studies suggest earlier puberty is associated with higher adulthood blood pressure (BP), but these findings have not been replicated using Mendelian randomization (MR). We examined this question sex-specifically using larger genome-wide association studies (GWAS) with more extensive measures of pubertal timing. Methods We obtained genetic instruments proxying pubertal maturation (age at menarche (AAM) or voice breaking (AVB)) from the largest published GWAS. We applied them to summary sex-specific genetic associations with systolic and diastolic BP z-scores, and self-reported hypertension in women (n=194174) and men (n=167020) from the UK Biobank, using inverse-variance weighting meta-analysis. We conducted sensitivity analyses using other MR methods, including multivariable MR adjusted for childhood obesity proxied by body mass index (BMI). We used late pubertal growth as a validation outcome. Results AAM (beta per one-year later = -0.030 [95% confidence interval (CI) -0.055, -0.005] and AVB (beta -0.058 [95% CI -0.100, -0.015]) were inversely associated with systolic BP independent of childhood BMI, as were diastolic BP (-0.035 [95% CI -0.060, -0.009] for AAM and -0.046 [95% CI -0.089, -0.004] for AVB) and self-reported hypertension (odds ratios 0.89 [95% CI 0.84, 0.95] for AAM and 0.87 [95% CI 0.79, 0.96] for AVB). AAM and AVB were positively associated with late pubertal growth, as expected. The results were robust to sensitivity analysis using other MR methods. Conclusion Timing of pubertal maturation was associated with adulthood BP independent of childhood BMI, highlighting the role of pubertal maturation timing in midlife BP.

scholarly journals Association of Thyroid Function with Blood Pressure and Cardiovascular Disease: A Mendelian Randomization

2021 ◽  
Vol 11 (12) ◽  
pp. 1306
Author(s):  
Alice Giontella ◽  
Luca A. Lotta ◽  
John D. Overton ◽  
Aris Baras ◽  
Andrea Sartorio ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Thyroid Function ◽  
Lower Risk ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Thyroid Peroxidase ◽  
Genome Wide Association Studies ◽  
Causal Association

Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper- or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study. Single nucleotide polymorphisms (SNPs) associated with thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), hyper- and hypothyroidism, and anti-thyroid peroxidase antibodies (TPOAb), from genome-wide association studies (GWAS), were selected as MR instrumental variables. SNPs–outcome (BP, CVD) associations were evaluated in a large-scale cohort, the Malmö Diet and Cancer Study (n = 29,298). Causal estimates were computed by inverse-variance weighted (IVW), weighted median, and MR-Egger approaches. Genetically increased levels of TSH were associated with decreased systolic BP and with a lower risk of atrial fibrillation. Hyperthyroidism and TPOAb were associated with a lower risk of atrial fibrillation. Our data support a causal association between genetically decreased levels of TSH and both atrial fibrillation and systolic BP. The lack of significance after Bonferroni correction and the sensitivity analyses suggesting pleiotropy, should prompt us to be cautious in their interpretation. Nevertheless, these findings offer mechanistic insight into the etiology of CVD. Further work into the genes involved in thyroid functions and their relation to cardiovascular outcomes may highlight pathways for targeted intervention.

scholarly journals Physical activity and risk of Alzheimer’s disease: a two-sample Mendelian randomization study

2019 ◽  
Author(s):  
Sebastian E Baumeister ◽  
André Karch ◽  
Martin Bahls ◽  
Alexander Teumer ◽  
Michael F Leitzmann ◽  
...  
Keyword(s):  
Physical Activity ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Observational Studies ◽  
Protective Factor ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Inverse Variance

ABSTRACTIntroductionEvidence from observational studies for the effect of physical activity on the risk of Alzheimer’s disease (AD) is inconclusive. We performed Mendelian randomization analysis to examine whether physical activity is a protective factor for AD.MethodsSummary data of genome-wide association studies on physical activity and AD were identified using PubMed and the GWAS catalog. The study population included 21,982 AD cases and 41,944 cognitively normal controls. Eight single nucleotide polymorphisms (SNP) known at P < 5×10−8 to be associated with accelerometer-assessed physical activity served as instrumental variables.ResultsGenetically predicted accelerometer-assessed physical activity had no effect on the risk of AD (inverse variance weighted odds ratio [OR] per standard deviation (SD) increment: 1.03, 95% confidence interval: 0.97-1.10, P=0.332).DiscussionThe present study does not support a relationship between physical activity and risk of AD, and suggests that previous observational studies might have been biased.

scholarly journals Investigating Casual Associations among Gut Microbiota, Metabolites and Neurodegenerative Diseases: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Jin-Tai Yu ◽  
Jing Ning ◽  
Shu-Yi Huang ◽  
Shi-Dong Chen ◽  
Yu-Xiang Yang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Neurodegenerative Diseases ◽  
Protective Factor ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Causal Relationships ◽  
Genome Wide ◽  
Underlying Mechanisms ◽  
Lateral Sclerosis

Abstract Background Recent studies had explored that the gut microbiota was associated with neurodegenerative diseases (including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear. Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites and neurodegenerative diseases through Mendelian randomization (MR) approach. Methods We selected genetic variants associated with gut microbiota traits (N = 18340) and gut microbiota-derived metabolites (N = 7824) from genome-wide association studies (GWASs). Summary statistics of neurodegenerative diseases were obtained from IGAP (AD: 17008 cases; 37154 controls), IPDGC (PD: 37 688 cases; 141779 controls) and IALSC (ALS: 20806 cases; 59804 controls) respectively. Results A total of 19 gut microbiota traits were found to be causally associated with risk of neurodegenerative diseases, including 1 phylum, 2 classes, 2 orders, 2 families and 12 genera. We found genetically predicted greater abundance of Ruminococcus, at genus level (OR:1.245, 95%CI:1.103,1.405; P = 0.0004) was significantly related to higher risk of ALS. We also found suggestive association between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. For serotonin pathway, our results revealed serotonin as protective factor of PD, and kynurenine as risk factor of ALS. Besides, reduction of glutamine was found causally associated with occurrence of AD. Conclusions Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites and the risk of AD, PD and ALS, and we revealed several causal relationships. These findings may provide new targets for treatment of these neurodegenerative diseases, and may offer valuable insights for further researches on the underlying mechanisms.

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.

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