scholarly journals Using genetic path analysis to control for pleiotropy in a Mendelian randomization study

2019 ◽  
Author(s):  
Frank D Mann ◽  
Andrey A Shabalin ◽  
Anna R Docherty ◽  
Robert F Krueger
Keyword(s):  
Body Mass Index ◽  
Path Analysis ◽  
Instrumental Variable ◽  
Mendelian Randomization ◽  
Smoking Initiation ◽  
Exclusion Criteria ◽  
Complex Phenotypes ◽  
Gene Environment ◽  
Polygenic Scores ◽  
Health Related

AbstractBackgroundWhen a randomized experimental study is not possible, Mendelian randomization studies use genetic variants or polygenic scores as instrumental variables to control for gene-environment correlation while estimating the association between an exposure and outcome. Polygenic scores have become increasingly potent predictors of their respective phenotypes, satisfying the relevance criteria of an instrumental variable. Evidence for pleiotropy, however, casts doubt on whether the exclusion criteria of an instrumental variable is likely to hold for polygenic scores of complex phenotypes, and a number of methods have been developed to adjust for pleiotropy in Mendelian randomization studies.MethodUsing multiple polygenic scores and path analysis we implement an extension of genetic instrumental variable regression, genetic path analysis, and use it to test whether educational attainment is associated with two health-related outcomes in adulthood, body mass index and smoking initiation, while estimating and controlling for both gene-environment correlations and pleiotropy.ResultsGenetic path analysis provides compelling evidence for a complex set of gene-environment transactions that undergird the relations between educational attainment and health-related outcomes in adulthood. Importantly, results are consistent with education having a protective effect on body mass index and smoking initiation, even after controlling for gene-environment correlations and pleiotropy.ConclusionsThe proposed method is capable of addressing the exclusion criteria for a sound instrumental variable and, consequently, has the potential to help advance Mendelian randomization studies of complex phenotypes.

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.

Complex Phenotypes and the Use of Polygenic Scores to Investigate Gene × Environment Interactions for Substance Use

2016 ◽  
Author(s):  
Michael Windle
Keyword(s):  
Candidate Gene ◽  
First Generation ◽  
Candidate Gene Approach ◽  
Sample Sizes ◽  
Complex Phenotypes ◽  
Gene Environment ◽  
Polygenic Scores ◽  
Visual Frame ◽  
The Many ◽  
Meta Analyses

The chapter suggests the need of a “second-generation” candidate gene approach to adapt to first-generation limitations and to strengthen efforts to study GE interactions. The sample sizes associated with many phenotypes and areas of study in the literature (e.g., clinical trials, neuroimaging studies) are unlikely to yield sample sizes in the area of GWA and NGS studies (i.e., 200,000-300,000 participants). However, by building upon prior limitations in the candidate gene literature, using findings from GWA and NGS studies and meta-analyses, using multiple methods of analyses (e.g., gene expression analysis; methylation analysis), and using theory and prior substantive research to guide hypothesis testing, progress can be made on G X E interactions for complex phenotypes. Several illustrative path models were provided in this chapter to provide a visual frame for how we have approached G X E interactions in the past, and how, going forward, we might proceed to investigate multiple polygenic by multiple environmental models. This level of complexity may be necessary to advance the field to address the many exciting research questions of interest, as well as the challenges that confront us as we attempt to move this knowledge from discovery to practice.

scholarly journals Interaction-based Mendelian randomization with measured and unmeasured gene-by-covariate interactions

2020 ◽  
Author(s):  
Wes Spiller ◽  
Fernando Pires Hartwig ◽  
Eleanor Sanderson ◽  
George Davey Smith ◽  
Jack Bowden
Keyword(s):  
Blood Pressure ◽  
Body Mass Index ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Uk Biobank ◽  
Gene Environment ◽  
Gxe Interactions ◽  
Using Data ◽  
The Uk ◽  
Positive Effect

Studies leveraging gene-environment (GxE) interactions within Mendelian randomization (MR) analyses have prompted the emergence of two methodologies: MR-GxE and MR-GENIUS. Such methods are attractive in allowing for pleiotropic bias to be corrected when using individual instruments. Specifically, MR-GxE requires an interaction to be explicitly identified, while MR-GENIUS does not. We critically examine the assumptions of MR-GxE and MR-GENIUS, and propose sensitivity analyses to evaluate their performance. Finally, we explore the association between body mass index (BMI) and systolic blood pressure (SBP) using data from the UK Biobank. We find both approaches share similar assumptions, though differences between the approaches lend themselves to differing research settings. Where interactions are identified, MR-GxE relies on weaker assumptions and allows for further sensitivity analyses. MR-GENIUS circumvents the need to identify interactions, but relies on the MR-GxE assumptions holding globally. Through applied analyses we find evidence of a positive effect of BMI upon SBP.

P–374 Investigating causality of risk factors for miscarriage – a Mendelian randomization analysis

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
J Painter ◽  
T Laisk ◽  
C Lindgren ◽  
S Medland
Keyword(s):  
Risk Factors ◽  
Body Mass Index ◽  
Risk Factor ◽  
Instrumental Variables ◽  
Genetic Variants ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Recurrent Miscarriage ◽  
Coffee Consumption ◽  
Smoking Initiation

Abstract Study question Do modifiable risk factors such as smoking, alcohol or coffee consumption, and adiposity causally increase the risk of sporadic or recurrent miscarriage? Summary answer We found evidence for a causal relationship between smoking initiation and sporadic miscarriage, but not for any other risk factor tested. What is known already Miscarriage is estimated to end between 10–25% of clinically confirmed pregnancies, and many observational studies have suggested numerous lifestyle factors, such as coffee and alcohol consumption, smoking and increased adiposity, may increase miscarriage risk. However, results are not always consistent across studies, and definitive causal relationships between various risk factors and miscarriage have not yet been demonstrated. Mendelian randomization utilizes genetic variants significantly associated with heritable risk factors (i.e. at P-values <5x10–8 in large genome-wide association studies) as instrumental variables to investigate causality of risk factors in population health outcomes. Study design, size, duration We conducted two-sample Mendelian randomization analyses to investigate causality of smoking (initiation and quantity), alcohol and coffee consumption (quantity), and adiposity (body mass index and waist-hip ratio) in sporadic and recurrent miscarriage. Data included in this study were taken from previously published summary genetic association statistics (betas, standard errors and P-values) from large-scale genome-wide association studies (GWAS) for each risk factor, and from our recently published GWAS of sporadic and recurrent miscarriage. Participants/materials, setting, methods Instrumental variables were constructed using 5–306 genetic variants significantly associated with the listed risk factors in published GWAS (minimum N = 178,000 individuals). Two instrumental variables were constructed per risk factor using data from different GWAS. Associations of the instrumental variables with miscarriage were investigated using summary association data from women of European ancestry included in our miscarriage GWAS, including 49,996 sporadic miscarriage cases and 174,109 female controls, and 750 recurrent miscarriage cases and 150,215 female controls. Main results and the role of chance We found a significant association between sporadic miscarriage and the instrumental variables for two smoking measures: smoking initiation (inverse variance weighted Odds Ratio = 1.17, 95% confidence intervals = 1.10–1.24, P = 2.7 x 10–07) and lifetime smoking (inverse variance weighted Odds Ratio = 1.22, 95% confidence intervals 1.11–1.35, P = 4.2x10–5). No other risk factors (smoking quantity, coffee or alcohol consumption, or BMI or waist-hip ratio) were associated with either sporadic or recurrent miscarriage. A priori power calculations considering the amount of phenotypic variance in each risk factor explained by the associated SNPs suggested our analysis to have at least 75% power to detect an association with Odds Ratio of 1.2 with sporadic miscarriage for analyses of body mass index, waist hip ratio and smoking initiation, quantity and the lifetime smoking measure, but that the alcohol and coffee consumption analyses were underpowered (4.9% and 48%, respectively). All analyses were underpowered for recurrent miscarriage given the small case sample size (N = 750). Limitations, reasons for caution While data utilised here come from large-scale GWAS including 1000s of individuals, genetic variants significantly associated with each risk factor currently explain small percentages (0.02–6%) of the variance in each trait. Larger GWAS for specific risk factors, and for sporadic and recurrent miscarriage, are required to clarify some published associations. Wider implications of the findings: We find no evidence of a causal link between adiposity and miscarriage, indicating that observational findings of increased miscarriage risk with increasing body mass index require further explanation. Significant associations between measures of ever-smoking and sporadic miscarriage highlights that no amount of smoking is safe in regards to miscarriage risk. Trial registration number Not applicable

scholarly journals Reporting methodological issues of the mendelian randomization studies in health and medical research: a systematic review

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Shabab Noor Islam ◽  
Tanvir Ahammed ◽  
Aniqua Anjum ◽  
Olayan Albalawi ◽  
Md. Jamal Uddin
Keyword(s):  
Systematic Review ◽  
Instrumental Variable ◽  
Mendelian Randomization ◽  
Least Square ◽  
Mr Studies ◽  
Risk Scores ◽  
Methodological Issues ◽  
Exclusion Criteria ◽  
Prisma Statement ◽  
Modelling Approach

Abstract Background Mendelian randomization (MR) studies using Genetic risk scores (GRS) as an instrumental variable (IV) have increasingly been used to control for unmeasured confounding in observational healthcare databases. However, proper reporting of methodological issues is sparse in these studies. We aimed to review published papers related to MR studies and identify reporting problems. Methods We conducted a systematic review using the clinical articles published between 2009 and 2019. We searched PubMed, Scopus, and Embase databases. We retrieved information from every MR study, including the tests performed to evaluate assumptions and the modelling approach used for estimation. Using our inclusion/exclusion criteria, finally, we identified 97 studies to conduct the review according to the PRISMA statement. Results Only 66 (68%) of the studies empirically verified the first assumption (Relevance assumption), and 40 (41.2%) studies reported the appropriate tests (e.g., R2, F-test) to investigate the association. A total of 35.1% clearly stated and discussed theoretical justifications for the second and third assumptions. 30.9% of the studies used a two-stage least square, and 11.3% used the Wald estimator method for estimating IV. Also, 44.3% of the studies conducted a sensitivity analysis to illuminate the robustness of estimates for violations of the untestable assumptions. Conclusions We found that incompleteness of the justification of the assumptions for the instrumental variable in MR studies was a common problem in our selected studies. This may misdirect the findings of the studies.

scholarly journals Differences in exercise capacity and health-related quality of life according to the body mass index in patients with COPD

Pulmonology ◽  
2021 ◽  
Author(s):  
Jhonatan Betancourt-Peña ◽  
Juan Carlos Ávila-Valencia ◽  
Diana Milena Diaz-Vidal ◽  
Vicente Benavides-Córdoba
Keyword(s):  
Quality Of Life ◽  
Body Mass Index ◽  
Exercise Capacity ◽  
Body Mass ◽  
The Body ◽  
Health Related Quality ◽  
Related Quality ◽  
Health Related

scholarly journals The impact of late-career job loss and genetic risk on body mass index: Evidence from variance polygenic scores

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lauren L. Schmitz ◽  
Julia Goodwin ◽  
Jiacheng Miao ◽  
Qiongshi Lu ◽  
Dalton Conley
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Complex Traits ◽  
Job Loss ◽  
Past Research ◽  
Long Term Effects ◽  
Polygenic Scores ◽  
Show Evidence ◽  
Using Data ◽  
The Impact

AbstractUnemployment shocks from the COVID-19 pandemic have reignited concerns over the long-term effects of job loss on population health. Past research has highlighted the corrosive effects of unemployment on health and health behaviors. This study examines whether the effects of job loss on changes in body mass index (BMI) are moderated by genetic predisposition using data from the U.S. Health and Retirement Study (HRS). To improve detection of gene-by-environment (G × E) interplay, we interacted layoffs from business closures—a plausibly exogenous environmental exposure—with whole-genome polygenic scores (PGSs) that capture genetic contributions to both the population mean (mPGS) and variance (vPGS) of BMI. Results show evidence of genetic moderation using a vPGS (as opposed to an mPGS) and indicate genome-wide summary measures of phenotypic plasticity may further our understanding of how environmental stimuli modify the distribution of complex traits in a population.

scholarly journals Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Shuai Yuan ◽  
Edward L. Giovannucci ◽  
Susanna C. Larsson
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Pancreatitis ◽  
Alcohol Consumption ◽  
Mendelian Randomization ◽  
Gallstone Disease ◽  
Smoking Initiation ◽  
Disease Type ◽  
Uk Biobank ◽  
Increased Risk

AbstractWe conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p < 5 × 10−8 were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.

scholarly journals Systematic Review: The Impact of Physical Activity on Risk and Health-Related Quality of Life in Bladder Cancer

2021 ◽  
pp. 1-10
Author(s):  
Marina Rodríguez Cintas ◽  
Sara Márquez ◽  
Javier González Gallego
Keyword(s):  
Quality Of Life ◽  
Physical Activity ◽  
Systematic Review ◽  
Metabolic Syndrome ◽  
Body Mass Index ◽  
Bladder Cancer ◽  
Health Related Quality ◽  
Related Quality ◽  
Health Related

BACKGROUND: Sedentarism is an important modifiable risk factor in the struggle against cancer. In the last decades, the relationship between physical activity and different types of cancer has been investigated in depth. OBJECTIVE: To provide an overview of the literature on the effectiveness of physical activity in reducing the risk to develop bladder cancer and improving health-related quality of life in patients. METHODS: A systematic review was conducted through a search of the Embase, Cochrane, PubMed, Scopus, and Web of Science (WOS) databases to seek information and PRISMA system to delimitate the research. Outcomes included in searches were physical activity, tobacco consumption, obesity, body mass index, and metabolic syndrome, associated with bladder cancer and quality of life. RESULTS: Database searches identified 394 records, of which 75 were duplicated. A total of 280 articles were excluded based on abstract screening. An additional 16 full-text articles were excluded because they did not meet the eligibility criteria. Overall, 21 of the 23 studies included in the review reported beneficial effects of physical activity in bladder cancer. The majority of papers found that physical activity is a significant factor in reducing the risk of bladder cancer. Moreover, physical activity improves health-related quality of life in bladder cancer survivors, and diminishes both recurrence and mortality in those who engage in regular activity. Lastly, physical inactivity is associated with increased body mass index, obesity, metabolic syndrome, type 2 diabetes and unfavourable energy balance, which led to a greater probability of suffering from bladder cancer. CONCLUSIONS: These data reinforce the importance of promoting a healthy lifestyle to reduce the risk of bladder cancer and to improve survivorship and health-related quality of life of patients.

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