Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways

Burgess, Stephen; Daniel, Rhian; Butterworth, Adam S.; Thompson, Simon G.

doi:10.1093/ije/dyu176

Cited by 356 publications

(335 citation statements)

References 47 publications

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“…18 A method called network Mendelian randomization was recently described to investigate whether some of the effect of an exposure on the outcome may operate through a mediating variable. 19 However, this kind of analysis is beyond the scope of our article.…”

Section: Association Of Single Nucleotide Polymorphisms With Uamentioning

confidence: 95%

Uric Acid and Cardiovascular Events

Kleber

Delgado

Grammer

et al. 2015

Journal of the American Society of Nephrology

239

156

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Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid-regulating single nucleotide polymorphisms. Causal odds ratios and causal hazard ratios (HRs) were calculated using a two-stage regression estimate with the GRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death.

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Section: Association Of Single Nucleotide Polymorphisms With Uamentioning

confidence: 95%

Uric Acid and Cardiovascular Events

Kleber

Delgado

Grammer

et al. 2015

Journal of the American Society of Nephrology

239

156

View full text Add to dashboard Cite

show abstract

“…Rather, if a sample has racially homogeneous ancestry and at least some of the population are heterozygous for a genetic polymorphism, the presence of that polymorphism in offspring may be regarded as randomly determined. This is the basis of Mendelian randomization analyses that consider genetic effects on an instrumental variable (e.g., hypnotics consumption) and an outcome variable (e.g., mortality) in order to estimate the component size of the causal pathway leading from genotype to hypnotics consumption to modified mortality [44][45][46][47]. Mendelian randomization eliminates the interference of most confounders in estimating causality, though there remain various complex issues that must be considered.…”

Section: Limitations Due To Genetic Effects and New Research Possibilmentioning

confidence: 99%

Mortality Risk of Hypnotics: Strengths and Limits of Evidence

Kripke

2015

Drug Saf

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Sleeping pills, more formally defined as hypnotics, are sedatives used to induce and maintain sleep. In a review of publications for the past 30 years, descriptive epidemiologic studies were identified that examined the mortality risk of hypnotics and related sedative-anxiolytics. Of the 34 studies estimating risk ratios, odds ratios, or hazard ratios, excess mortality associated with hypnotics was significant (p \ 0.05) in 24 studies including all 14 of the largest, contrasted with no studies at all suggesting that hypnotics ever prolong life. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications; possible genetic confounders; and too much heterogeneity of studies for meta-analyses. There were balancing limitations possibly tending towards underestimates of risk such as limited power, excessive follow-up intervals with possible follow-up mixing of participants taking hypnotics with controls, missing dosage data for most studies, and over-adjustment of confounders. Epidemiologic association in itself is not adequate proof of causality, but there is proof that hypnotics cause death in overdoses; there is thorough understanding of how hypnotics euthanize animals and execute humans; and there is proof that hypnotics cause potentially lethal morbidities such as depression, infection, poor driving, suppressed respiration, and possibly cancer. Combining these proofs with consistent evidence of association, the great weight of evidence is that hypnotics cause huge risks of decreasing a patient's duration of survival. Key PointsMost sleeping pills e.g., benzodiazepines and ''Z'' benzodiazepine agonists (like eszopiclone) are associated with early death, and they most probably cause serious increases in mortality.Benzodiazepine agonist sleeping pills and diphenhydramine should not be prescribed for insomnia, except in long-term controlled trials and hospice care.

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“…Mendelian randomisation (MR) is a tool using genetic variants as instrumental variables (IVs) to evaluate whether a risk factor is causally associated with an outcome 11. The objective of this study was to search out whether or not years of education is causally related with the development of RA employing a MR analysis.…”

Section: Introductionmentioning

confidence: 99%

Causal relationship between years of education and the occurrence of rheumatoid arthritis

Bae

Lee

2019

Postgraduate Medical Journal

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ObjectiveTo search out whether or not years of education is causally related to rheumatoid arthritis (RA).MethodWe conducted a two-sample Mendelian randomisation (MR) analysis employing inverse-variance weighted (IVW), weighted median and MR-Egger regression analysis. We chose statistic data of years of education from the UK Biobank genome-wide association studies (GWASs) (n=293 723) as the exposure and a meta-analysis of GWASs of RA with autoantibody (n=5539) and European controls (n=20 169) as the outcome.ResultsWe selected a total of 49 single nucleotide polymorphisms as instrumental variables (IVs). The IVW method instructed an inverse causative relationship between years of education and RA (β=− 0.039, SE=0.283, p=0.008). MR-Egger regression test showed that directional pleiotropy seems not to bias the MR results (intercept=0.028; p=0.358). MR-Egger analysis demonstrated no causative relationship between RA and years of education (β=− 2.320, SE=1.709, p=0.181). However, the weighted median approach indicated a causative association between RA and years of education (β=−0.950, SE=0.355, p=0.008).ConclusionsThe MR analysis supported a potential inverse causative relationship between years of education and development of RA.

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Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways

Cited by 356 publications

References 47 publications

Uric Acid and Cardiovascular Events

Uric Acid and Cardiovascular Events

Mortality Risk of Hypnotics: Strengths and Limits of Evidence

Causal relationship between years of education and the occurrence of rheumatoid arthritis

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