scholarly journals OP96 The causal effect of BMI on neurodevelopment: a within family mendelian randomization study using MoBa

2020 ◽  
Author(s):  
AM Hughes ◽  
H Ask ◽  
T Tesli ◽  
RB Askeland ◽  
T Reichborn-Kjennerud ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Causal Effect

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

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.

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 Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

2021 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
Kate Tilling ◽  
George Davey Smith ◽  
Deborah A Lawlor ◽  
Maria Carolina Borges
Keyword(s):  
Waist Circumference ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Real Data ◽  
Sensitivity Analyses ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

scholarly journals The Causal Effect of Vitamin D Binding Protein (DBP) Levels on Calcemic and Cardiometabolic Diseases: A Mendelian Randomization Study

PLoS Medicine ◽  
2014 ◽  
Vol 11 (10) ◽  
pp. e1001751 ◽  
Author(s):  
Aaron Leong ◽  
Waheed Rehman ◽  
Zari Dastani ◽  
Celia Greenwood ◽  
Nicholas Timpson ◽  
...  
Keyword(s):  
Vitamin D ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Binding Protein ◽  
Vitamin D Binding Protein ◽  
Cardiometabolic Diseases

scholarly journals Using genetic variants to evaluate the causal effect of serum vitamin D concentration on COVID-19 susceptibility, severity and hospitalization traits: a Mendelian randomization study

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhiyong Cui ◽  
Yun Tian
Keyword(s):  
Vitamin D ◽  
Fixed Effects ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Serum Vitamin ◽  
Vitamin D Supplementation ◽  
Sensitivity Analyses ◽  
Global Test ◽  
Serum Vitamin D

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has struck globally and is exerting a devastating toll on humans. The pandemic has led to calls for widespread vitamin D supplementation in public. However, evidence supporting the role of vitamin D in the COVID-19 pandemic remains controversial. Methods We performed a two-sample Mendelian randomization (MR) analysis to analyze the causal effect of the 25-hydroxyvitamin D [25(OH)D] concentration on COVID-19 susceptibility, severity and hospitalization traits by using summary-level GWAS data. The causal associations were estimated with inverse variance weighted (IVW) with fixed effects (IVW-fixed) and random effects (IVW-random), MR-Egger, weighted edian and MR Robust Adjusted Profile Score (MR.RAPS) methods. We further applied the MR Steiger filtering method, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test and PhenoScanner tool to check and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. Results We found no evidence to support the causal associations between the serum 25(OH)D concentration and the risk of COVID-19 susceptibility [IVW-fixed: odds ratio (OR) = 0.9049, 95% confidence interval (CI) 0.8197–0.9988, p = 0.0473], severity (IVW-fixed: OR = 1.0298, 95% CI 0.7699–1.3775, p = 0.8432) and hospitalized traits (IVW-fixed: OR = 1.0713, 95% CI 0.8819–1.3013, p = 0.4878) using outlier removed sets at a Bonferroni-corrected p threshold of 0.0167. Sensitivity analyses did not reveal any sign of horizontal pleiotropy. Conclusions Our MR analysis provided precise evidence that genetically lowered serum 25(OH)D concentrations were not causally associated with COVID-19 susceptibility, severity or hospitalized traits. Our study did not provide evidence assessing the role of vitamin D supplementation during the COVID-19 pandemic. High-quality randomized controlled trials are necessary to explore and define the role of vitamin D supplementation in the prevention and treatment of COVID-19.

Clinical Research on Antioxidant-Based Modalities in 2021

2021 ◽  
Vol 11 ◽  
Author(s):  
Editorial Office ROS
Keyword(s):  
Vitamin C ◽  
Mediterranean Diet ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Biological Activities ◽  
Controlled Trial ◽  
Positive Finding ◽  
Randomized Controlled ◽  
The Us ◽  
Anti Inflammatory

Being updated biweekly till the end of the year, this Education & Resources web page lists major clinical studies on antioxidant-based modalities or related entities in disease intervention and health promotion, which have been published in highly influential journals during 2021. It should be noted that this is not intended to be a complete list, but is rather to focus on rigorously designed and well conducted high-profile randomized controlled trials (RCTs) whose findings were reported in medical or bioscience journals of the highest impact. For more comprehensive information on antioxidant-based clinical trials, the reader may refer to the ClinicalTrials.gov (https://clinicaltrials.gov), the largest clinical trials database, run by the US National Library of Medicine, that holds registrations from over 368,000 trials from 219 countries. 2021 LIST IN REVERSE CHRONOLOGICAL ORDER Xu et al. Edaravone dexborneol versus edaravone alone for the treatment of acute ischemic stroke: a phase III, randomized, double-blind, comparative trial. Stroke 2021 Mar; 52(3):772-780. doi: https://dx.doi.org/10.1161/STROKEAHA.120.031197. Key finding: Edaravone dexborneol (a combination of edaravone and borneol) was superior to edaravone alone in improving the clinical outcomes of the acute ischemic stroke patients. Note: Edaravone, a synthetic free radical scavenger, was approved by the US FDA in 2017 for treating amyotrophic lateral sclerosis (ALS). Borneol is a phytochemical with diverse biological activities including antioxidative and anti-inflammatory effects. Kim et al. Reactive oxygen species scavenger in acute intracerebral hemorrhage patients: a multicenter, randomized controlled trial. Stroke 2021 Feb 25; doi: https://doi.org/10.1161/STROKEAHA.120.032266. Key finding: Giving N-acetylcysteine 2000 mg/day and selenium 1600 µg/day, intravenously, for 14 days significantly improved the clinical outcomes in the acute intracerebral hemorrhage patients. Note: N-Acetylcysteine is a precursor of glutathione (GSH). Selenium acts as an antioxidant element due, at least partly, to its essentialness for the function of various selenoproteins, including selenium-dependent glutathione peroxidases (GPx). Kalstad et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 2021 Feb 9; 143(6):528-539. doi: https://dx.doi.org/10.1161/CIRCULATIONAHA.120.052209. Key finding: Null Note: n-3 Fatty acids, also known as omega-3 fatty acids, possess potent antioxidative and anti-inflammatory activities. Lynch et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann Neurol 2021 Feb; 89(2):212-225. doi: https://dx.doi.org/10.1002/ana.25934. Key finding: Omaveloxolone significantly improved neurological function compared to placebo and is well tolerated. Note: Omaveloxolone, a synthetic oleanane triterpenoid, is an activator of Nrf2, the chief regulator of cellular antioxidant and other cytoprotective genes. Meir et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut 2021 Jan 18; gutjnl-2020-323106. doi: https://dx.doi.org/10.1136/gutjnl-2020-323106. Key finding: Green-Mediterranean diet enriched with green plants and polyphenols improved non-alcoholic fatty liver disease (NAFLD). Note: Mediterranean diet and green plants (green tea) and nuts are rich in antioxidants and anti-inflammatory compounds and possess many health benefits, especially cardiovascular protection. However, the exact contribution of antioxidant components to the health benefits of Mediterranean diet remains to be established. Rinott et al. Effects of diet-modulated autologous fecal microbiota transplantation on weight regain. Gastroenterology 2021 Jan; 160(1):158-173.e10. doi: https://dx.doi.org/10.1053/j.gastro.2020.08.041. Key finding: Polyphenol-enriched diet-modulated autologous fecal microbiota transplantation attenuated weight regain and preserved glycemic control. Note: Dietary polyphenols possess antioxidative, anti-inflammatory, and many other biological activities. Zheng et al. Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations. Diabetes Care 2021 Jan; 44(1):98-106. doi: https://dx.doi.org/10.2337/dc20-1328. Key finding: Null; no evidence to support an efficacy of vitamin C supplement in type 2 diabetes prevention. Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions. According to Dr Davey Smith,  Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship. Luo et al. Diet-derived circulating antioxidants and risk of coronary heart disease: a Mendelian randomization study. J Am Coll Cardiol 2021 Jan 5; 77(1):45-54. doi: https://dx.doi.org/10.1016/j.jacc.2020.10.048. Key finding: Null Note: According to Dr Davey Smith,  Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship.

scholarly journals Assessing the Causality Factors in the Association between (Abdominal) Obesity and Physical Activity among the Newfoundland Population–-A Mendelian Randomization Analysis

2016 ◽  
Vol 8 ◽  
pp. GEG.S38289 ◽  
Author(s):  
Frank Barning ◽  
Taraneh Abarin
Keyword(s):  
Physical Activity ◽  
Newfoundland And Labrador ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Intervention Strategies ◽  
Nucleotide Polymorphisms ◽  
Fto Gene ◽  
Single Nucleotide ◽  
Similar Association ◽  
Randomization Analysis

A total of 1,263 adults from Newfoundland and Labrador were studied in the research. Body mass index (BMI) and percent trunk fat (PTF) were analyzed as biomarkers for obesity. The Mendelian randomization (MR) approach with two single-nucleotide polymorphisms in the fat-mass and obesity (FTO) gene as instruments was employed to assess the causal effect. In both genders, increasing physical activity significantly reduced BMI and PTF when adjusted for age and the FTO gene. The effect of physical activity was stronger on PTF than BMI. Direct observational analyses showed significant increase in BMI/PTF when physical activity decreased. A similar association in MR analyses was not significant. The association between physical activity and BMI/PTF could be due to reversed causality or common confounding factors. Our study provides insights into the causal contributions of obesity to physical activity in adults. Health intervention strategies to increase physical activity among adults should include some other plans such as improving diet for reducing obesity.

scholarly journals A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuquan Wang ◽  
Tingting Li ◽  
Liwan Fu ◽  
Siqian Yang ◽  
Yue-Qing Hu
Keyword(s):  
Linkage Disequilibrium ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Random Effect ◽  
Pleiotropic Effect ◽  
Genome Wide Association Studies ◽  
The Novel ◽  
Novel Method

Mendelian randomization makes use of genetic variants as instrumental variables to eliminate the influence induced by unknown confounders on causal estimation in epidemiology studies. However, with the soaring genetic variants identified in genome-wide association studies, the pleiotropy, and linkage disequilibrium in genetic variants are unavoidable and may produce severe bias in causal inference. In this study, by modeling the pleiotropic effect as a normally distributed random effect, we propose a novel mixed-effects regression model-based method PLDMR, pleiotropy and linkage disequilibrium adaptive Mendelian randomization, which takes linkage disequilibrium into account and also corrects for the pleiotropic effect in causal effect estimation and statistical inference. We conduct voluminous simulation studies to evaluate the performance of the proposed and existing methods. Simulation results illustrate the validity and advantage of the novel method, especially in the case of linkage disequilibrium and directional pleiotropic effects, compared with other methods. In addition, by applying this novel method to the data on Atherosclerosis Risk in Communications Study, we conclude that body mass index has a significant causal effect on and thus might be a potential risk factor of systolic blood pressure. The novel method is implemented in R and the corresponding R code is provided for free download.

scholarly journals Causal Effect Between Total Cholesterol and HDL Cholesterol as Risk Factors for Chronic Kidney Disease: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Liu Miao ◽  
Yan Min ◽  
Chuan-Meng Zhu ◽  
Jian-Hong Chen ◽  
Bin Qi ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Hdl Cholesterol ◽  
Causal Effects ◽  
Lipid Levels ◽  
Serum Lipid Levels ◽  
Genome Wide ◽  
Mr Study

Abstract Background/Aims: While observational studies show an association between serum lipid levels and cardiovascular disease (CVD), intervention studies that examine the preventive effects of serum lipid levels on the development of CKD are lacking. Methods: To estimate the role of serum lipid levels in the etiology of CKD, we conducted a two-sample Mendelian randomization (MR) study on serum lipid levels. Single nucleotide polymorphisms (SNPs), which were significantly associated genome-wide with plasma serum lipid levels from the GLGC and CKDGen consortium genome-wide association study (GWAS), including total cholesterol (TC, n = 187365), triglyceride (TG, n = 177861), HDL cholesterol (HDL-C, n = 187167), LDL cholesterol (LDL-C, n = 173082), apolipoprotein A1 (ApoA1, n = 20687), apolipoprotein B (ApoB, n = 20690) and CKD (n = 117165), were used as instrumental variables. None of the lipid-related SNPs was associated with CKD (all P > 0.05). Results: MR analysis genetically predicted the causal effect between TC/HDL-C and CKD. The odds ratio (OR) and 95% confidence interval (CI) of TC within CKD was 0.756 (0.579 to 0.933) (P = 0.002), and HDL-C was 0.85 (0.687 to 1.012) (P = 0.049). No causal effects between TG, LDL-C- ApoA1, ApoB and CKD were observed. Sensitivity analyses confirmed that TC and HDL-C were significantly associated with CKD. Conclusions: The findings from this MR study indicate causal effects between TC, HDL-C and CKD. Decreased TC and elevated HDL-C may reduce the incidence of CKD but need to be further confirmed by using a genetic and environmental approach.

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