scholarly journals Smoking, DNA methylation and lung function: a Mendelian randomization analysis to investigate causal relationships

2019 ◽  
Author(s):  
Emily Jamieson ◽  
Roxanna Korologou-Linden ◽  
Robyn E. Wootton ◽  
Anna L. Guyatt ◽  
Thomas Battram ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lung Function ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Forced Expiratory Volume ◽  
Multiple Trait ◽  
Genome Wide ◽  
Causal Variants ◽  
Association Data ◽  
Randomization Analysis

AbstractWhether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in one second (FEV1) in two-sample Mendelian randomization (MR) using methylation quantitative trait loci and genome-wide association data for FEV1. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p<1.2×10−4). Replication analysis supported a causal effect at three CpGs (cg21201401 (ZGPAT), cg19758448 (PGAP3) and cg12616487 (AHNAK) (p<0.0028). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites may influence lung function via effects on smoking. Using multiple-trait colocalization, we found evidence of shared causal variants between lung function, gene expression and DNA methylation. Findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although large, tissue-specific datasets are required to confirm these results.

scholarly journals Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways

2020 ◽  
Vol 106 (3) ◽  
pp. 315-326 ◽  
Author(s):  
Emily Jamieson ◽  
Roxanna Korologou-Linden ◽  
Robyn E. Wootton ◽  
Anna L. Guyatt ◽  
Thomas Battram ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lung Function ◽  
Mendelian Randomization ◽  
Causal Pathways ◽  
Mendelian Randomization Analysis ◽  
Randomization Analysis

scholarly journals Estimating the causal effect of genetic liability to prevalent disease on hospital costs using Mendelian Randomization

2020 ◽  
Author(s):  
Padraig Dixon ◽  
Sean Harrison ◽  
William Hollingworth ◽  
Neil M Davies ◽  
George Davey Smith
Keyword(s):  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Hospital Costs ◽  
Disease Status ◽  
Uk Biobank ◽  
Inpatient Hospital ◽  
Genome Wide ◽  
Split Sample ◽  
Randomization Analysis

BACKGROUND Accurate measurement of the effects of disease status on healthcare cost is important in the pragmatic evaluation of interventions but is complicated by endogeneity biases due to omitted variables and reverse causality. Mendelian Randomization, the use of random perturbations in germline genetic variation as instrumental variables, can avoid these limitations. We report a novel Mendelian Randomization analysis of the causal effect of liability to disease on healthcare costs. METHODS We used Mendelian Randomization to model the causal impact on inpatient hospital costs of liability to six highly prevalent diseases: asthma, eczema, migraine, coronary heart disease, type 2 diabetes, and major depressive disorder. We identified genetic variants from replicated genome-wide associations studies and estimated their association with inpatient hospital costs using data from UK Biobank, a large prospective cohort study of individuals linked to records of hospital care. We assessed potential violations of the instrumental variable assumptions, particularly the exclusion restriction (i.e. variants affecting costs through alternative paths). We also conducted new genome wide association studies of hospital costs within the UK Biobank cohort as a further split sample sensitivity analysis. RESULTS We analyzed data on 307,032 individuals. Genetic variants explained only a small portion of the variance in each disease phenotype. Liability to coronary heart disease had substantial impacts (mean per person per year increase in costs from allele score Mendelian Randomization models: 712 pounds sterling (95% confidence interval: 238 pounds to 1,186 pounds)) on inpatient hospital costs in causal analysis, but other results were imprecise. There was concordance of findings across varieties of sensitivity analyses, including stratification by sex, and those obtained from the split sample analysis. CONCLUSION A novel Mendelian Randomization analysis of the causal effect of liability to disease on healthcare cost demonstrates that this type of analysis is feasible and informative in this context. There was concordance across data sources and across methods bearing different assumptions. Selection into the relatively healthy UK Biobank cohort and the modest proportion of variance in disease status accounted for by the allele scores reduced the precision of our estimates. We therefore could not exclude the possibility of substantial costs due to these diseases.

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 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 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.

scholarly journals Mendelian randomization analyses reveal mediating factors of the causal effect of height on coronary artery disease

2021 ◽  
Author(s):  
Daniel Hui ◽  
Christopher S. Thom ◽  
Kimberly Lorenz ◽  
Scott M. Damrauer ◽  
Themistocles L. Assimes ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Lung Function ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Multivariable Analysis ◽  
Inverse Correlation ◽  
Artery Disease ◽  
Cad Risk

An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested evidence that this association may be causal. However, the extent to which the effect estimated by MR can be explained by established cardiovascular risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized the largest set of genetic instruments for human stature to date, comprising >2,000 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height (~6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 2.1x10-2). We observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest that height does not add meaningful clinical impact on CAD risk prediction beyond established risk factors.

scholarly journals The effect of body mass index on smoking behaviour and nicotine metabolism: a Mendelian randomization study

2018 ◽  
Author(s):  
Amy E. Taylor ◽  
Rebecca C. Richmond ◽  
Teemu Palviainen ◽  
Anu Loukola ◽  
Jaakko Kaprio ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Dna Methylation ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Smoking Initiation ◽  
Smoking Behaviour ◽  
Bidirectional Association ◽  
Metabolite Ratio ◽  
Nicotine Metabolite Ratio

AbstractBackgroundGiven clear evidence that smoking lowers weight, it is possible that individuals with higher body mass index (BMI) smoke in order to lose or maintain their weight.Methods and FindingsWe undertook Mendelian randomization analyses using 97 genetic variants associated with BMI. We performed two sample Mendelian randomization analyses of the effects of BMI on smoking behaviour in UK Biobank (N=335,921) and the Tobacco and Genetics consortium genomewide association study (GWAS) (N≤74,035) respectively, and two sample Mendelian randomization analyses of the effects of BMI on cotinine levels (N≤4,548) and nicotine metabolite ratio (N≤1,518) in published GWAS, and smoking-related DNA methylation in the Avon Longitudinal Study of Parents and Children (N≤846).In inverse variance weighted Mendelian randomization analysis, there was evidence that higher BMI was causally associated with smoking initiation (OR for ever vs never smoking per one SD increase in BMI: 1.19, 95% CI: 1.11 to 1.27) and smoking heaviness (1.45 additional cigarettes smoked per day per SD increase in BMI, 95% CI: 1.03 to 1.86), but little evidence for a causal effect with smoking cessation. Results were broadly similar using pleiotropy robust methods (MR-Egger, median and weighted mode regression). These results were supported by evidence for a causal effect of BMI on DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus. There was no strong evidence that BMI was causally associated with cotinine, but suggestive evidence for a causal negative association with the nicotine metabolite ratio.ConclusionsThere is a causal bidirectional association between BMI and smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism. It may be useful to consider BMI and smoking together when designing prevention strategies to minimise the effects of these risk factors on health outcomes.

Long-term PM2.5 Exposure, Genome-wide DNA Methylation and Lung Function in Korean Adults

2021 ◽  
Author(s):  
Ye-Eun Han ◽  
Nak-Hyeon Choi ◽  
Mi Jin Cho ◽  
Min Gu Kang ◽  
Young-Youl Kim
Keyword(s):  
Dna Methylation ◽  
Lung Function ◽  
Korean Adults ◽  
Genome Wide ◽  
Pm2.5 Exposure
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