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Inferring the direction of a causal link and estimating its effect via a Bayesian Mendelian randomization approach.

ABSTRACT: The use of genetic variants as instrumental variables - an approach known as Mendelian randomization - is a popular epidemiological method for estimating the causal effect of an exposure (phenotype, biomarker, risk factor) on a disease or health-related outcome from observational data. Instrumental variables must satisfy strong, often untestable assumptions, which means that finding good genetic instruments among a large list of potential candidates is challenging. This difficulty is compounded by the fact that many genetic variants influence more than one phenotype through different causal pathways, a phenomenon called horizontal pleiotropy. This leads to errors not only in estimating the magnitude of the causal effect but also in inferring the direction of the putative causal link. In this paper, we propose a Bayesian approach called BayesMR that is a generalization of the Mendelian randomization technique in which we allow for pleiotropic effects and, crucially, for the possibility of reverse causation. The output of the method is a posterior distribution over the target causal effect, which provides an immediate and easily interpretable measure of the uncertainty in the estimation. More importantly, we use Bayesian model averaging to determine how much more likely the inferred direction is relative to the reverse direction.

SUBMITTER: Bucur IG

PROVIDER: S-EPMC7221461 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Inferring the direction of a causal link and estimating its effect via a Bayesian Mendelian randomization approach.

Bucur Ioan Gabriel IG Claassen Tom T Heskes Tom T

Statistical methods in medical research 20190530 4

The use of genetic variants as instrumental variables - an approach known as Mendelian randomization - is a popular epidemiological method for estimating the causal effect of an exposure (phenotype, biomarker, risk factor) on a disease or health-related outcome from observational data. Instrumental variables must satisfy strong, often untestable assumptions, which means that finding good genetic instruments among a large list of potential candidates is challenging. This difficulty is compounded ...[more]

PMID: 31146640

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Project description:IntroductionMetabolic syndrome (MetS) is significantly associated with osteoarthritis (OA), especially in MetS patients with blood glucose abnormalities, such as elevated fasting blood glucose (FG), which may increase OA risk. Dietary modifications, especially the intake of polyunsaturated fatty acids (PUFAs), are regarded as a potential means of preventing MetS and its complications. However, regarding the effects of FG, Omega-3s, and Omega-6s on OA, the research conclusions are conflicting, which is attributed to the complexity of the pathogenesis of OA. Therefore, it is imperative to thoroughly evaluate multiple factors to fully understand their role in OA, which needs further exploration and clarification.MethodsTwo-sample univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were employed to examine the causal effect of metabolic related factors on hip OA (HOA) or knee OA (KOA). The exposure and outcome datasets were obtained from Open GWAS IEU. All cases were independent European ancestry data. Three MR methods were performed to estimate the causal effect: inverse-variance weighting (IVW), weighted median method (WMM), and MR-Egger regression. Additionally, the intercept analysis in MR-Egger regression is used to estimate pleiotropy, and the IVW method and MR-Egger regression are used to test the heterogeneity.ResultsThe UVMR analysis revealed a causal relationship between FG and HOA. By MVMR analysis, the study discovered a significant link between FG (OR = 0.79, 95%CI: 0.64∼0.99, p = 0.036) and KOA after accounting for body mass index (BMI), age, and sex hormone-binding globulin (SHBG). However, no causal effects of FG on HOA were seen. Omega-3s and Omega-6s did not have a causal influence on HOA or KOA. No significant evidence of pleiotropy was identified.DiscussionThe MR investigation showed a protective effect of FG on KOA development but no causal relationship between FG and HOA. No causal effect of Omega-3s and Omega-6s on HOA and KOA was observed. Shared genetic overlaps might also exist between BMI and age, SHBG and PUFAs for OA development. This finding offers a novel insight into the treatment and prevention of KOA from glucose metabolism perspective. The FG cutoff value should be explored in the future, and consideration should be given to demonstrating the study in populations other than Europeans.

Project description:BackgroundAs the number of COVID-19 deaths continues to rise worldwide, the identification of risk factors for the disease is an urgent issue, and it remains controversial whether atherogenic lipid-related traits including serum apolipoprotein B, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels, are risk factors. The aim of this study was to estimate causal effects of lipid-related traits on COVID-19 risk in the European population using a two-sample Mendelian randomization (MR) approach.MethodsWe used summary statistics from a genome-wide association study (GWAS) that included 441,016 participants from the UK Biobank as the exposure dataset of lipid-related traits and from COVID-19 Host Genetics Initiative GWAS meta-analyses of European ancestry as the outcome dataset for COVID-19 susceptibility (32,494 cases and 1,316,207 controls), hospitalization (8316 cases and 1,549,095 controls), and severity (4792 cases and 1,054,664 controls). We performed two-sample MR analyses using the inverse variance weighted (IVW) method. As sensitivity analyses, the MR-Egger regression, weighted median, and weighted mode methods were conducted as were leave-one-out sensitivity analysis, the MR-PRESSO global test, PhenoScanner searches, and IVW multivariable MR analyses. A P value below 0.0055 with Bonferroni correction was considered statistically significant.ResultsThis MR study suggested that serum apolipoprotein B or LDL-cholesterol levels were not significantly associated with COVID-19 risk. On the other hand, we inferred that higher serum triglyceride levels were suggestively associated with higher risks of COVID-19 susceptibility (odds ratio [OR] per standard deviation increase in lifelong triglyceride levels, 1.065; 95% confidence interval [CI], 1.001-1.13; P = 0.045) and hospitalization (OR, 1.174; 95% CI, 1.04-1.33; P = 0.012), and were significantly associated with COVID-19 severity (OR, 1.274; 95% CI, 1.08-1.50; P = 0.004). Sensitivity and bidirectional MR analyses suggested that horizontal pleiotropy and reverse causation were unlikely.ConclusionsOur MR study indicates a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity in the European population using the latest and largest GWAS datasets to date. However, as the underlying mechanisms remain unclear and our study might be still biased due to possible horizontal pleiotropy, further studies are warranted to validate our findings and investigate underlying mechanisms.

Project description:BackgroundFrailty index and vestibular disorders appear to be associated in observational studies, but causality of the association remains unclear.MethodsA two-sample Mendelian randomization (MR) study was implemented to explore the causal relationship between the frailty index and vestibular disorders in individuals of European descent. A genome-wide association study (GWAS) of frailty index was used as the exposure (n = 175, 226), whereas the GWAS of vestibular disorders was the outcome (n = 462,933). MR Steiger filtering method was conducted to investigate the causal effect of the frailty index on vestibular disorders. An inverse variance weighted (IVW) approach was used as the essential approach to examine the causality. Additionally, the MR-Egger methods, the simple mode analysis, the weighted median analysis, and the weighted mode analysis were used as supplementary methods. The MR-PRESSO analysis, the MR-Egger intercept analysis, and Cochran's Q statistical analysis also were used to detect the possible heterogeneity as well as directional pleiotropy. To evaluate this association, the odds ratio (OR) with 95% confidence intervals (CIs) was used. All statistical analyses were performed in R. The STROBE-MR checklist for the reporting of MR studies was used in this study.ResultsIn total, 14 single nucleotide polymorphisms (SNPs) were identified as effective instrumental variables (IVs) in the two sample MR analyses. The significant causal effect of the frailty index on vestibular disorders was demonstrated by IVW method [OR 1.008 (95% CI 1.003, 1.013), p = 0.001]. Results from the various sensitivity analysis were consistent. The "leave-one-out" analysis indicated that our results were robust even without a single SNP. According to the MR-Egger intercept test [intercept = -0.000151, SE = 0.011, p = 0.544], genetic pleiotropy did not affect the results. No heterogeneity was detected by Cochran's Q test. Results of MR Steiger directionality test indicated the accuracy of our estimate of the potential causal direction (Steiger p < 0.001).ConclusionThe MR study suggested that genetically predicted frailty index may be associated with an increased risk of vestibular disorders. Notably, considering the limitations of this study, the causal effects between frailty index and vestibular disorders need further investigation. These results support the importance of effectively managing frailty which may minimize vestibular disorders and improve the quality of life for those with vestibular disorders.

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Inferring the direction of a causal link and estimating its effect via a Bayesian Mendelian randomization approach.

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Inferring the direction of a causal link and estimating its effect via a Bayesian Mendelian randomization approach.

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