Caution against examining the role of reverse causality in Mendelian Randomization

2021 ◽  
Author(s):  
Sharon M. Lutz ◽  
Ann Chen Wu ◽  
John E. Hokanson ◽  
Stijn Vansteelandt ◽  
Christoph Lange
Keyword(s):  
Mendelian Randomization ◽  
Reverse Causality

The Role of Morning Plasma Cortisol in Obesity: A Bi-directional Mendelian Randomization Study

2022 ◽  
Author(s):  
Xiaohui QI ◽  
Bin CUI ◽  
Min CAO
Keyword(s):  
Genetic Variants ◽  
Plasma Cortisol ◽  
Mendelian Randomization ◽  
Class Ii ◽  
Class I ◽  
Class Iii ◽  
Reverse Causality ◽  
Obese People ◽  
Obesity Class

Abstract Context Cortisol, an important hormone regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is associated with obesity. However, it is unclear whether the relationship between cortisol and obesity is causal or could be explained by reverse causality. Objective This work aims to assess the role of morning plasma cortisol in clinical classes of obesity. Methods In this bi-directional two-sample Mendelian Randomization (MR) study, cortisol-associated genetic variants were obtained from the CORtisol NETwork consortium (n = 12,597). The primary outcomes were obesity class I (BMI ≥ 30 kg/m 2), class II (BMI ≥ 35 kg/m 2), and class III (BMI ≥ 40kg/m 2). Inverse variance weighting (IVW) method was used as the main analysis, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. Conversely, genetic variants predicting clinical classes of obesity were applied to the cortisol GWAS. Results Genetically predicted cortisol was associated with reduced risk of obesity class I (OR = 0.905; 95% CI, 0.865-0.946; p < 0.001). Evidence from bi-directional MR showed that obesity class II and class III were associated with lower cortisol levels ((class II-cortisol OR = 0.953; 95% CI, 0.923-0.983; p = 0.002); (class III-cortisol OR = 0.955; 95% CI, 0.942-0.967; p < 0.001)), indicating reverse causality between cortisol and obesity. Conclusions This study demonstrates that cortisol is negatively associated with obesity and vice versa. Together, these findings suggest that blunted morning plasma cortisol secretion may be responsible for severe obesity. Regulating morning plasma secretion might be a prevention measure for obese people.

scholarly journals Role of educational attainment, cognitive performance and intelligence in neurodegeneration: a bidirectional Mendelian randomization study

2019 ◽  
Author(s):  
Sandeep Grover ◽  
Keyword(s):  
Educational Attainment ◽  
Neurodegenerative Diseases ◽  
Cognitive Performance ◽  
Mendelian Randomization ◽  
Late Onset ◽  
Age Related Macular Degeneration ◽  
European Ancestry ◽  
Reverse Causality ◽  
Age Related

AbstractI examined the potential bi-directional causality between educational attainment (EA) (n = 766,345) and age related macular degeneration (AMD) (cases (n) =16144, controls (n) =17832) using the summary GWAS datasets on individuals with European ancestry. I used datasets on other late-onset neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD) as controls to validate the findings. A risky effect of EA on AMD was observed (OR=1.318, 95% CI=1.080 −1.610, P=0.0068) after ruling out potential pleiotropy and absence of reverse causality. I further replicated previously observed protective and risky causal associations of EA with AD and PD.

scholarly journals The role of linoleic acid in asthma and inflammatory markers: a Mendelian randomization study

2019 ◽  
Vol 110 (3) ◽  
pp. 685-690 ◽  
Author(s):  
Jie V Zhao ◽  
C Mary Schooling
Keyword(s):  
Linoleic Acid ◽  
Blood Cell ◽  
White Blood Cell ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Uk Biobank ◽  
Reverse Causality ◽  
The Uk

ABSTRACT Background Asthma is a common respiratory disease, possibly caused by autoimmunity. Linoleic acid (LA), the main n–6 (ω-6) PUFA from widely used vegetable oils, is thought to suppress immune responses that might have benefits for asthma. However, this question has not been examined in randomized controlled trials. Objectives To obtain unconfounded estimates, we assessed how genetically predicted LA affected asthma using 2-sample Mendelian randomization. We also examined its role in white blood cell traits (eosinophil, neutrophil, and low monocyte counts) identified as potential causal factors in asthma. Methods We used 18 uncorrelated, genome-wide significant genetic variants to predict LA, which we applied to a large genetic case (n = 19,954)–control (n = 107,715) study of asthma, to the UK Biobank (408,961 people of European ancestry with 26,332 asthma cases), and for white blood cell traits to the UK Biobank. We also repeated the analysis on asthma using 29 replicated, functionally relevant genetic variants. In addition, we examined the role of asthma in LA to assess reverse causality. Results Genetically predicted LA was associated with lower risk of asthma (OR: 0.89 per SD increase in LA; 95% CI: 0.85, 0.93), with no association of asthma with LA. Genetically predicted LA was associated with lower eosinophil count (−0.03; 95% CI: −0.061, −0.004) and lower neutrophil count (−0.04; 95% CI: −0.057, −0.023). These estimates were robust to different selections of genetic variants and sensitivity analyses. Conclusions LA might protect against asthma possibly via white blood cell traits, with relevance to the identification of effective new interventions for asthma.

scholarly journals 146Mendelian randomisation for mediation analysis: current methods and challenges for implementation

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Alice Carter ◽  
Eleanor Sanderson ◽  
Gemma Hammerton ◽  
Rebecca Richmond ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Measurement Error ◽  
Causal Inference ◽  
Mediation Analysis ◽  
Mendelian Randomization ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
Reverse Causality ◽  
Single Model ◽  
Instrument Bias

Abstract Background Mendelian randomisation uses genetic variants randomly allocated at conception as instrumental variables for an exposure. Methodological advances allow for mediation analysis to be carried out using Mendelian randomisation using either multivariable Mendelian randomisation or two-step Mendelian randomisation. Methods We use simulations and an applied example to demonstrate when multivariable Mendelian randomisation and two-step Mendelian randomisation methods are valid and how they relate to traditional phenotypic regression-based approaches to mediation. We demonstrate how Mendelian randomisation methods can relax assumptions required for causal inference in phenotypic mediation, as well as which Mendelian randomisation specific assumptions are required. We illustrate our methods in data from UK Biobank, estimating the role of body mass index mediating the association between education and cardiovascular outcomes. Results Both multivariable Mendelian randomization and two-step Mendelian randomization are unbiased when estimating the total effect, direct effect, indirect effect and proportion mediated when both confounding, and measurement error are present. Multivariable Mendelian Randomization can be used when multiple mediators are to be investigated in a single model. Conclusions Mendelian randomisation provides an opportunity to improve causal inference in mediation analysis. Although Mendelian randomisation specific assumptions apply, such as no weak instrument bias and no pleiotropic pathways, strong phenotypic assumptions of no confounding and no measurement error can be relaxed. Key messages Mendelian randomisation offers an opportunity to address bias by unmeasured confounding, measurement error and reverse causality in mediation analysis.

scholarly journals Uric Acid and Hypertension: Prognostic Role and Guide for Treatment

2021 ◽  
Vol 10 (3) ◽  
pp. 448
Author(s):  
Federica Piani ◽  
Arrigo F. G. Cicero ◽  
Claudio Borghi
Keyword(s):  
Clinical Trials ◽  
Uric Acid ◽  
Mendelian Randomization ◽  
Strong Association ◽  
Epidemiological Studies ◽  
Hypertensive Disease ◽  
Genetic Studies ◽  
Lowering Therapy ◽  
The Relationship

The relationship between serum uric acid (SUA) and hypertension has been a subject of increasing interest since the 1870 discovery by Frederick Akbar Mahomed. Several epidemiological studies have shown a strong association between high SUA levels and the presence or the development of hypertension. Genetic analyses have found that xanthine oxidoreductase (XOR) genetic polymorphisms are associated with hypertension. However, genetic studies on urate transporters and Mendelian randomization studies failed to demonstrate a causal relationship between SUA and hypertension. Results from clinical trials on the role of urate-lowering therapy in the management of patients with hypertension are not uniform. Our study sought to analyze the prognostic and therapeutic role of SUA in the hypertensive disease, from uric acid (UA) biology to clinical trials on urate-lowering therapies.

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.

Stroke Genetics: Turning Discoveries into Clinical Applications

Stroke ◽  
2021 ◽  
Author(s):  
Martin Dichgans ◽  
Nathalie Beaufort ◽  
Stephanie Debette ◽  
Christopher D. Anderson
Keyword(s):  
Mendelian Randomization ◽  
Association Studies ◽  
Clinical Applications ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Neuroprotective Agents ◽  
Experimental Systems ◽  
Genome Wide ◽  
Rapid Pace

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

scholarly journals Causal role of L-glutamine in sickle cell disease painful crises: a Mendelian randomization analysis

2019 ◽  
Author(s):  
Yann Iboudo ◽  
Melanie E. Garrett ◽  
Pablo Bartolucci ◽  
Carlo Brugnara ◽  
Clary B. Clish ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Small Molecules ◽  
Causal Relationship ◽  
Sickle Cell ◽  
Drug Targets ◽  
Mendelian Randomization ◽  
Cell Disease ◽  
Aseptic Necrosis ◽  
Randomization Analysis

ABSTRACTIn a recent clinical trial, the metabolite L-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To confirm this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a causal relationship between L-glutamine levels and painful crises (N=1,278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52 – 0.89], P=0.0048). In two smaller SCD cohorts (N=299 and 406), the protective effect of L-glutamine was observed (OR=0.82 [0.50-1.34]), although the MR result was not significant (P=0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid was associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.

scholarly journals Remittances and Income Smoothing

2011 ◽  
Vol 101 (3) ◽  
pp. 582-587 ◽  
Author(s):  
Catalina Amuedo-Dorantes ◽  
Susan Pozo
Keyword(s):  
Developing Countries ◽  
Household Income ◽  
Borrowing Constraints ◽  
Income Smoothing ◽  
Reverse Causality ◽  
Income Volatility ◽  
Household Level ◽  
Level Data ◽  
Main Motive

Due to inadequate savings and binding borrowing constraints, income volatility can make households in developing countries particularly susceptible to economic hardship. We examine the role of remittances in either alleviating or increasing household income volatility using Mexican household level data over the 2000 through 2008 period. We correct for reverse causality and endogeneity and find that while income smoothing does not appear to be the main motive for sending remittances in a non-negligible share of households, remittances do indeed smooth household income on average. Other variables surrounding income volatility are also considered and evaluated.

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