Treatment of Metformin Decreases the Risk of Varicose Vein: A Mendelian Randomization Study

Abstract Background Varicose vein is a common illness of the vascular system which affects life quality and social function of patients. We aimed to assess the causality between metformin and varicose vein using a two-sample Mendelian randomization（MR）analysis based on genome-wide association study (GWAS) summary data.Methods Twenty-five single nucleotide polymorphisms (SNPs) were selected from the GWAS summary data from Neale Lab and MRC-IEU Consortium available on the MR-base platform. Inverse variance weighted (IVW), MR-egger method, weighted median method and weighted mode were adopted. Results were evaluated by pleiotropy test using an Egger regression method and sensitivity analysis preforming a leaving-one-out (LOO) method. Analyses were performed using R package “TwoSampleMR”.Results The result of IVW method showed that one SD increased treatment of metformin was linked with approximately 10% lower risk of varicose vein (OR,0.90; 95%CI, 0.85-0.96; P, 6.99e-04). It was similar to that measured by other methods in the aspect of effect size and direction. There is no evidence to supporting genetic pleiotropy in the MR-Egger regression method (intercept=2.5e-04, P=0.33). No single SNP was detected to be strongly driving the overall causal effect in a LOO sensitivity analysis. The genetically predicted treatment of metformin was negatively casually associated with varicose veins.Conclusions This study suggested that treatment of metformin was a casual protective factor of varicose vein. Further researches are required to confirm our findings and explore the potential mechanisms of metformin on varicose vein.

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

International Journal of Stroke ◽

10.1177/17474930211006285 ◽

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<5Ã10-8) 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=1.48Ã10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01Ã10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16Ã10-4). 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.

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A Preliminary Report on Alcohol-Associated DNA Methylation Changes and Suicidal Behavior: Evidence Using Mendelian Randomization

Illness Crisis & Loss ◽

10.1177/1054137320952246 ◽

2021 ◽

pp. 105413732095224

Author(s):

Charleen D. Adams

Keyword(s):

Public Health ◽

Dna Methylation ◽

Suicidal Behavior ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Economic Stress ◽

Self Report ◽

Health Concern ◽

The Us

Suicide is a major public health concern. In 2015, it was the 10th leading cause of death in the US. The number of suicides increased by 30% in the US from 1999 to 2016, and a greater uptick in suicides is predicted to occur as a result of the COVID-19 crisis, for which the primary public-health strategy is physical distancing and during which alcohol sales have soared. Thus, current strategies for identifying at-risk individuals and preventing suicides, such as relying on self-reported suicidal ideation, are insufficient, especially under conditions of physical distancing, which exacerbate isolation, loneliness, economic stress, and possibly alcohol consumption. New strategies are urgent now and into the future. To that aim, here, a two-sample Mendelian randomization (an instrumental variables technique using public genome-wide association study data as data sources) was performed to determine whether alcohol-associated changes in DNA methylation mediate risk for suicidal behavior. The results suggest that higher alcohol-associated DNA methylation levels at cg18120259 confer a weak causal effect. Replication and triangulation of the results, both experimentally and with designs other than Mendelian randomization, are needed. If the findings replicate, the information might be utilized to raise awareness about the biological links between alcohol and suicide and possibly explored as a biomarker of risk, perhaps especially for early detection of those who may not self-report suicidal intent.

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Using a Two-Sample Mendelian Randomization Method in Assessing the Causal Relationships Between Human Blood Metabolites and Heart Failure

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.695480 ◽

2021 ◽

Vol 8 ◽

Author(s):

Zixian Wang ◽

Shiyu Chen ◽

Qian Zhu ◽

Yonglin Wu ◽

Guifeng Xu ◽

...

Keyword(s):

Heart Failure ◽

Human Blood ◽

Large Scale ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Sensitivity Analyses ◽

Blood Metabolites ◽

Causal Relationships

Background: Heart failure (HF) is the main cause of morbidity and mortality worldwide, and metabolic dysfunction is an important factor related to HF pathogenesis and development. However, the causal effect of blood metabolites on HF remains unclear.Objectives: Our chief aim is to investigate the causal relationships between human blood metabolites and HF risk.Methods: We used an unbiased two-sample Mendelian randomization (MR) approach to assess the causal relationships between 486 human blood metabolites and HF risk. Exposure information was obtained from Sample 1, which is the largest metabolome-based genome-wide association study (mGWAS) data containing 7,824 Europeans. Outcome information was obtained from Sample 2, which is based on the results of a large-scale GWAS meta-analysis of HF and contains 47,309 cases and 930,014 controls of Europeans. The inverse variance weighted (IVW) model was used as the primary two-sample MR analysis method and followed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis.Results: We observed that 11 known metabolites were potentially related to the risk of HF after using the IVW method (P < 0.05). After adding another four MR models and performing sensitivity analyses, we found a 1-SD increase in the xenobiotics 4-vinylphenol sulfate was associated with ~22% higher risk of HF (OR [95%CI], 1.22 [1.07–1.38]).Conclusions: We revealed that the 4-vinylphenol sulfate may nominally increase the risk of HF by 22% after using a two-sample MR approach. Our findings may provide novel insights into the pathogenesis underlying HF and novel strategies for HF prevention.

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Causal Association Between Heart Failure and Alzheimer’s Disease: A Two-Sample Bidirectional Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.772343 ◽

2022 ◽

Vol 12 ◽

Author(s):

Chenglin Duan ◽

Jingjing Shi ◽

Guozhen Yuan ◽

Xintian Shou ◽

Ting Chen ◽

...

Keyword(s):

Heart Failure ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sensitivity Analysis ◽

Causal Relationship ◽

Observational Studies ◽

Mendelian Randomization ◽

Causal Effect ◽

Causal Relationships ◽

Simple Mode

Background: Traditional observational studies have demonstrated an association between heart failure and Alzheimer’s disease. The strengths of observational studies lie in their speed of implementation, cost, and applicability to rare diseases. However, observational studies have several limitations, such as uncontrollable confounders. Therefore, we employed Mendelian randomization of genetic variants to evaluate the causal relationships existing between AD and HF, which can avoid these limitations.Materials and Methods: A two-sample bidirectional MR analysis was employed. All datasets were results from the UK’s Medical Research Council Integrative Epidemiology Unit genome-wide association study database, and we conducted a series of control steps to select the most suitable single-nucleotide polymorphisms for MR analysis, for which five primary methods are offered. We reversed the functions of exposure and outcomes to explore the causal direction of HF and AD. Sensitivity analysis was used to conduct several tests to avoid heterogeneity and pleiotropic bias in the MR results.Results: Our MR studies did not support a meaningful causal relationship between AD on HF (MR-Egger, p = 0.634 > 0.05; weighted median (WM), p = 0.337 > 0.05; inverse variance weighted (IVW), p = 0.471 > 0.05; simple mode, p = 0.454 > 0.05; weighted mode, p = 0.401 > 0.05). At the same time, we did not find a significant causal relationship between HF and AD with four of the methods (MR-Egger, p = 0.195 > 0.05; IVW, p = 0.0879 > 0.05; simple mode, p = 0.170 > 0.05; weighted mode, p = 0.110 > 0.05), but the WM method indicated a significant effect of HF on AD (p = 0.025 < 0.05). Because the statistical powers of IVW and MR-Egger are more than that of WM, we think that there is no causal effect of HF on AD. Sensitivity analysis and horizontal pleiotropy were not detected in the MR analysis.Conclusion: Our results did not provide significant evidence indicating any causal relationships between HF and AD in the European population. Therefore, more large-scale datasets or datasets related to similar factors are expected for further MR analysis.

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Using the MR-Base platform to investigate risk factors and drug targets for thousands of phenotypes

Wellcome Open Research ◽

10.12688/wellcomeopenres.15334.2 ◽

2019 ◽

Vol 4 ◽

pp. 113 ◽

Cited By ~ 12

Author(s):

Venexia M Walker ◽

Neil M Davies ◽

Gibran Hemani ◽

Jie Zheng ◽

Philip C Haycock ◽

...

Keyword(s):

Risk Factors ◽

Web Application ◽

Drug Targets ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

R Package ◽

Sensitivity Analyses ◽

Link Type ◽

Study Results

Mendelian randomization (MR) estimates the causal effect of exposures on outcomes by exploiting genetic variation to address confounding and reverse causation. This method has a broad range of applications, including investigating risk factors and appraising potential targets for intervention. MR-Base has become established as a freely accessible, online platform, which combines a database of complete genome-wide association study results with an interface for performing Mendelian randomization and sensitivity analyses. This allows the user to explore millions of potentially causal associations. MR-Base is available as a web application or as an R package. The technical aspects of the tool have previously been documented in the literature. The present article is complementary to this as it focuses on the applied aspects. Specifically, we describe how MR-Base can be used in several ways, including to perform novel causal analyses, replicate results and enable transparency, amongst others. We also present three use cases, which demonstrate important applications of Mendelian randomization and highlight the benefits of using MR-Base for these types of analyses.

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Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab329 ◽

2021 ◽

Author(s):

Christa Meisinger ◽

Dennis Freuer

Keyword(s):

Inflammatory Bowel Disease ◽

Atopic Dermatitis ◽

Bowel Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

The Other ◽

Uk Biobank ◽

Inflammatory Bowel ◽

The Uk

Abstract Background Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. Methods To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Results Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn’s disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. Conclusions This study supports a causal effect between AD and IBD—but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

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Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study

Psychological Medicine ◽

10.1017/s0033291716003172 ◽

2016 ◽

Vol 47 (5) ◽

pp. 971-980 ◽

Cited By ~ 82

Author(s):

S. H. Gage ◽

H. J. Jones ◽

S. Burgess ◽

J. Bowden ◽

G. Davey Smith ◽

...

Keyword(s):

Fixed Effects ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Positive Control ◽

Negative Control ◽

Study Data ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Genome Wide Data

BackgroundObservational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data.MethodWe performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation (p < 10−5) and schizophrenia (p < 5 × 10−8) were combined using an inverse-variance-weighted fixed-effects approach. We also used height and education genome-wide association study data, representing negative and positive control analyses.ResultsThere was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia [odds ratio (OR) 1.04 per doubling odds of cannabis initiation, 95% confidence interval (CI) 1.01–1.07, p = 0.019]. There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per doubling of the odds of schizophrenia, 95% CI 1.05–1.14, p = 2.64 × 10−5). Findings were as predicted for the negative control (height: OR 1.00, 95% CI 0.99–1.01, p = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97–1.00, p = 0.066) analyses.ConclusionsOur results provide some that cannabis initiation increases the risk of schizophrenia, although the size of the causal estimate is small. We find stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation.

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Parathyroid Hormone and Bone Mineral Density: A Mendelian Randomization Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa579 ◽

2020 ◽

Vol 105 (11) ◽

Author(s):

Zihao Qu ◽

Fangkun Yang ◽

Jianqiao Hong ◽

Wei Wang ◽

Shigui Yan

Keyword(s):

Bone Mineral Density ◽

Parathyroid Hormone ◽

Bone Mineral ◽

Large Scale ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Age Groups ◽

Mineral Density ◽

Serum Pth

Abstract Purpose Accumulating evidence implicates parathyroid hormone (PTH) in the development of osteoporosis. However, the causal effect of PTH on bone mineral density (BMD) remains unclear. Thus, this study is aimed at exploring the association between the concentrations of serum PTH and BMD. Methods The instrumental variables for PTH were selected from a large-scale genome-wide association study (GWAS; n = 29 155). Outcomes included BMD of the forearm (FA; n = 8143), femoral neck (FN; n = 33 297), lumbar spine (LS; n = 32 735), heel (HL; n = 394 929), and risk of fractures in these bones (n = 361 194). Furthermore, the BMD of 5 different age groups: 15 years or younger (n = 11 807), 15–30 (n = 4180), 30–45 (n = 10 062), 45–60 (n = 18 805), and 60 years or older (n = 22 504) were extracted from a GWAS meta-analysis study. The analyses were performed using the 2-sample Mendelian randomization method. Results Mendelian randomization analysis revealed that the level of serum PTH was inversely associated with BMD of FA (95% CI: -0.763 to -0.016), FN (95% CI: -0.669 to -0.304), and LS (95% CI: -0.667 to -0.243). A causal relationship between serum PTH levels and BMD was observed in individuals aged 30–45 (95% CI: -0.888 to -0.166), 45–60 (95% CI: -0.758 to -0.232), and over 60 years (95% CI: -0.649 to -0.163). Main Conclusions This study demonstrated that the concentrations of serum PTH is inversely associated with BMD of several bones. Further analysis revealed site- and age-specific correlations between serum PTH levels and BMD, which implies that the levels of serum PTH contribute to the development of osteoporosis.

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Using a two-sample Mendelian randomization design to investigate a possible causal effect of maternal lipid concentrations on offspring birth weight

International Journal of Epidemiology ◽

10.1093/ije/dyz160 ◽

2019 ◽

Vol 48 (5) ◽

pp. 1457-1467 ◽

Cited By ~ 14

Author(s):

Liang-Dar Hwang ◽

Deborah A Lawlor ◽

Rachel M Freathy ◽

David M Evans ◽

Nicole M Warrington

Keyword(s):

Birth Weight ◽

Standard Deviation ◽

Structural Equation ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

European Ancestry ◽

The Impact

Abstract Background The intrauterine environment is critical for fetal growth and development. However, observational associations between maternal gestational lipid concentrations and offspring birth weight (BW) have been inconsistent and ascertaining causality is challenging. Methods We used a novel two-sample Mendelian randomization (MR) approach to estimate the causal effect of maternal gestational high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride concentrations on offspring BW. Single nucleotide polymorphisms (SNPs) associated with serum HDL-C, LDL-C and triglyceride concentrations identified in the Global Lipids Genetics Consortium genome-wide association study meta-analysis (n = 188 577 European-ancestry individuals; sample 1) were selected as instrumental variables. The effects of these SNPs on offspring BW were estimated using a structural equation model in the UK Biobank and Early Growth Genetics consortium (n = 230 069 European-ancestry individuals; sample 2) that enabled partitioning of the genetic associations into maternal- (intrauterine) and fetal-specific effects. Results We found no evidence for a causal effect of maternal gestational HDL-C, LDL-C or triglyceride concentrations on offspring BW [standard deviation change in BW per standard deviation higher in HDL-C = −0.005 (95% confidence interval: −0.039, 0.029), LDL-C = 0.014 (−0.017, 0.045), and triglycerides = 0.014 (−0.025, 0.052)]. Conclusions Our findings suggest that maternal gestational HDL-C, LDL-C and triglyceride concentrations play a limited role in determining offspring BW. However, we cannot comment on the impact of these and other lipid fractions on fetal development more generally. Our study illustrates the power and flexibility of two-sample MR in assessing the causal effect of maternal environmental exposures on offspring outcomes.

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A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer

Nature Communications ◽

10.1038/s41467-020-19822-6 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Mark Gormley ◽

Tom Dudding ◽

Eleanor Sanderson ◽

Richard M. Martin ◽

Steven Thomas ◽

...

Keyword(s):

Standard Deviation ◽

Alcohol Consumption ◽

Oropharyngeal Cancer ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Strong Association ◽

Smoking Behaviour ◽

Standard Deviation Increase ◽

Independent Effects

AbstractThe independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.

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