scholarly journals The use of negative control outcomes in Mendelian Randomisation to detect potential population stratification or selection bias

2020 ◽  
Author(s):  
Eleanor Sanderson ◽  
Tom G Richardson ◽  
Gibran Hemani ◽  
George Davey Smith
Keyword(s):  
Selection Bias ◽  
Genetic Variants ◽  
Population Stratification ◽  
Epidemiological Studies ◽  
Negative Control ◽  
Mendelian Randomisation ◽  
Hair Colour ◽  
Potential Population ◽  
The Relationship ◽  
Mr Study

AbstractA key assumption of Mendelian randomisation (MR) analysis is that there is no association between the genetic variants used as instruments and the outcome other than through the exposure of interest. Two ways in which this assumption can be violated are through population stratification and selection bias which can introduce confounding of the relationship between the genetic variants and the outcome and so induce an association between them. Negative control outcomes are increasingly used to detect unobserved confounding in observational epidemiological studies. Here we consider the use of negative control outcomes in MR studies. As a negative control outcome in an MR study we propose the use of phenotypes which are determined before the exposure and outcome but which are likely to be subject to the same confounding as the exposure or outcome of interest. We illustrate our method with a two-sample MR analysis of a preselected set of exposures on self-reported tanning ability and hair colour. Our results show that, of the 33 exposures considered, GWAS studies of adiposity and education related traits are likely to be subject to population stratification and/or selection bias that is not controlled for through adjustment and so any MR study including these traits may be subject to bias that cannot be identified through standard pleiotropy robust methods.

scholarly journals The use of negative control outcomes in Mendelian randomization to detect potential population stratification

2021 ◽  
Author(s):  
Eleanor Sanderson ◽  
Tom G Richardson ◽  
Gibran Hemani ◽  
George Davey Smith
Keyword(s):  
Genetic Variants ◽  
Population Stratification ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Negative Control ◽  
Mr Studies ◽  
Genome Wide Association Studies ◽  
Potential Population ◽  
Mr Study

Abstract A key assumption of Mendelian randomization (MR) analysis is that there is no association between the genetic variants used as instruments and the outcome other than through the exposure of interest. One way in which this assumption can be violated is through population stratification, which can introduce confounding of the relationship between the genetic variants and the outcome and so induce an association between them. Negative control outcomes are increasingly used to detect unobserved confounding in observational epidemiological studies. Here we consider the use of negative control outcomes in MR studies to detect confounding of the genetic variants and the exposure or outcome. As a negative control outcome in an MR study, we propose the use of phenotypes which are determined before the exposure and outcome but which are likely to be subject to the same confounding as the exposure or outcome of interest. We illustrate our method with a two-sample MR analysis of a preselected set of exposures on self-reported tanning ability and hair colour. Our results show that, of the 33 exposures considered, genome-wide association studies (GWAS) of adiposity and education-related traits are likely to be subject to population stratification that is not controlled for through adjustment, and so any MR study including these traits may be subject to bias that cannot be identified through standard pleiotropy robust methods. Negative control outcomes should therefore be used regularly in MR studies to detect potential population stratification in the data used.

scholarly journals Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis

2021 ◽  
Author(s):  
Richard Culliford ◽  
Alex J. Cornish ◽  
Philip J. Law ◽  
Susan M. Farrington ◽  
Kimmo Palin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Large Scale ◽  
Causal Effect ◽  
Gallstone Disease ◽  
Epidemiological Studies ◽  
Mendelian Randomisation ◽  
Linear Relationships ◽  
Potential Risk Factors ◽  
The Relationship ◽  
Circulating Levels

Abstract Background Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). Methods We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. Results No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96–1.03, P value = 0.90) with CRC was shown. Conclusions Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.

scholarly journals Mendelian randomisation with coarsened exposures

2020 ◽  
Author(s):  
Matthew J. Tudball ◽  
Jack Bowden ◽  
Rachael A. Hughes ◽  
Amanda Ly ◽  
Marcus R. Munafò ◽  
...  
Keyword(s):  
Genetic Variance ◽  
Epidemiological Studies ◽  
Simple Expression ◽  
Effect Sizes ◽  
Mendelian Randomisation ◽  
Exposure Measurement ◽  
Continuous Trait ◽  
The One ◽  
The Relationship ◽  
Genetic Instruments

AbstractA key assumption in Mendelian randomisation is that the relationship between the genetic instruments and the outcome is fully mediated by the exposure, known as the exclusion restriction assumption. However, in epidemiological studies, the exposure is often a coarsened approximation to some latent continuous trait. For example, latent liability to schizophrenia can be thought of as underlying the binary diagnosis measure. Genetically-driven variation in the outcome can exist within categories of the exposure measurement, thus violating this assumption. We propose a framework to clarify this violation, deriving a simple expression for the resulting bias and showing that it may inflate or deflate effect estimates but will not reverse their sign. We then characterise a set of assumptions and a straight-forward method for estimating the effect of standard deviation increases in the latent exposure. Our method relies on a sensitivity parameter which can be interpreted as the genetic variance of the latent exposure. We show that this method can be applied in both the one-sample and two-sample settings. We conclude by demonstrating our method in an applied example and re-analysing two papers which are likely to suffer from this type of bias, allowing meaningful interpretation of their effect sizes.

Migraine: Genetic Variants and Clinical Phenotypes

2019 ◽  
Vol 26 (34) ◽  
pp. 6207-6221 ◽  
Author(s):  
Innocenzo Rainero ◽  
Alessandro Vacca ◽  
Flora Govone ◽  
Annalisa Gai ◽  
Lorenzo Pinessi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Mthfr Gene ◽  
Genome Wide Association Studies ◽  
Clinical Phenotypes ◽  
Network Analyses ◽  
Genome Wide ◽  
Genomic Studies ◽  
The Common ◽  
The Relationship

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

Potential Role of Inflammation in Associations between Particulate Matter and Heart Failure

2018 ◽  
Vol 24 (3) ◽  
pp. 341-358 ◽  
Author(s):  
Xiaotong Ji ◽  
Yingying Zhang ◽  
Guangke Li ◽  
Nan Sang
Keyword(s):  
Heart Failure ◽  
Particulate Matter ◽  
Inflammatory Response ◽  
Heart Diseases ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Inflammatory Mechanism ◽  
High Concentrations ◽  
Future Work ◽  
The Relationship

Recently, numerous studies have found that particulate matter (PM) exposure is correlated with increased hospitalization and mortality from heart failure (HF). In addition to problems with circulation, HF patients often display high expression of cytokines in the failing heart. Thus, as a recurring heart problem, HF is thought to be a disorder characterized in part by the inflammatory response. In this review, we intend to discuss the relationship between PM exposure and HF that is based on inflammatory mechanism and to provide a comprehensive, updated evaluation of the related studies. Epidemiological studies on PM-induced heart diseases are focused on high concentrations of PM, high pollutant load exposure in winter, or susceptible groups with heart diseases, etc. Furthermore, it appears that the relationship between fine or ultrafine PM and HF is stronger than that between HF and coarse PM. However, fewer studies paid attention to PM components. As for experimental studies, it is worth noting that coarse PM may indirectly promote the inflammatory response in the heart through systematic circulation of cytokines produced primarily in the lungs, while ultrafine PM and its components can enter circulation and further induce inflammation directly in the heart. In terms of PM exposure and enhanced inflammation during the pathogenesis of HF, this article reviews the following mechanisms: hemodynamics, oxidative stress, Toll-like receptors (TLRs) and epigenetic regulation. However, many problems are still unsolved, and future work will be needed to clarify the complex biologic mechanisms and to identify the specific components of PM responsible for adverse effects on heart health.

Adolescent smoking behavior and communication with parents: Depression as a mediator and gender as a moderator

2019 ◽  
Vol 47 (10) ◽  
pp. 1-9 ◽  
Author(s):  
Xieping Chen ◽  
Qian Xie ◽  
Yuting Yang
Keyword(s):  
Smoking Behavior ◽  
Depression Scale ◽  
Epidemiological Studies ◽  
Adolescent Smoking ◽  
Junior High Schools ◽  
Test Results ◽  
Negative Effect ◽  
And Gender ◽  
The Relationship ◽  
Communication Scale

Parent–adolescent communication is assumed to be an important factor affecting adolescent smoking behavior. However, the inner mechanism accounting for this association has still not been clarified in research. Our purpose in this study was to examine the relationships between parent–adolescent communication, adolescent smoking behavior, and depression, as well as gender differences in the relationship between depression and adolescent smoking behavior. Participants were 1,134 students at 6 junior high schools in China who completed the Parent-Adolescent Communication Scale, the Epidemiological Studies Depression Scale, and the Smoking Behavior Test. Results showed that parent-adolescent communication had a significant negative effect on adolescent smoking behavior and depression partially mediated the relationship between parent–adolescent communication and adolescent smoking behavior. In addition, gender moderated the relationship between depression and adolescent smoking behavior. Overall, these findings may help to promote better understanding of the relationship between parent–adolescent communication and adolescent smoking behavior.

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 Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease

2021 ◽  
Author(s):  
Andrew A. Crawford ◽  
◽  
Sean Bankier ◽  
Elisabeth Altmaier ◽  
Catriona L. K. Barnes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Genetic Variants ◽  
Plasma Cortisol ◽  
Statistical Power ◽  
Mendelian Randomisation ◽  
Eqtl Analysis ◽  
Causative Role ◽  
Peripheral Tissues ◽  
Corticosteroid Binding Globulin

AbstractThe stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

THE RELATIONSHIP BETWEEN OBSTRUCTIVE SLEEP APNOEA AND TASK-1 GENETIC VARIANTS

2018 ◽  
Vol 36 (Supplement 1) ◽  
pp. e205
Author(s):  
N. Li ◽  
T. Shi ◽  
X. Yao ◽  
Y. Wang ◽  
M. Heizhati ◽  
...  
Keyword(s):  
Obstructive Sleep Apnoea ◽  
Genetic Variants ◽  
Sleep Apnoea ◽  
Obstructive Sleep ◽  
The Relationship ◽  
And Task

scholarly journals Genetic evidence for a causative effect of airflow obstruction on left ventricular filling: a Mendelian randomisation study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lars Harbaum ◽  
Jan K. Hennigs ◽  
Marcel Simon ◽  
Tim Oqueka ◽  
Henrik Watz ◽  
...  
Keyword(s):  
General Population ◽  
Genetic Variants ◽  
Airflow Obstruction ◽  
Left Ventricular ◽  
Sensitivity Analyses ◽  
Weighted Regression ◽  
Mendelian Randomisation ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Inverse Variance

Abstract Background Observational studies on the general population have suggested that airflow obstruction associates with left ventricular (LV) filling. To limit the influence of environmental risk factors/exposures, we used a Mendelian randomisation (MR) approach based on common genetic variations and tested whether a causative relation between airflow obstruction and LV filling can be detected. Methods We used summary statistics from large genome-wide association studies (GWAS) on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) measured by spirometry and the LV end-diastolic volume (LVEDV) as assessed by cardiac magnetic resonance imaging. The primary MR was based on an inverse variance weighted regression. Various complementary MR methods and subsets of the instrument variables were used to assess the plausibility of the findings. Results We obtained consistent evidence in our primary MR analysis and subsequent sensitivity analyses that reducing airflow obstruction leads to increased inflow to the LV (odds ratio [OR] from inverse variance weighted regression 1.05, 95% confidence interval [CI] 1.01–1.09, P = 0.0172). Sensitivity analyses indicated a certain extent of negative horizontal pleiotropy and the estimate from biased-corrected MR-Egger was adjusted upward (OR 1.2, 95% CI 1.09–1.31, P < 0.001). Prioritisation of single genetic variants revealed rs995758, rs2070600 and rs7733410 as major contributors to the MR result. Conclusion Our findings indicate a causal relationship between airflow obstruction and LV filling in the general population providing genetic context to observational associations. The results suggest that targeting (even subclinical) airflow obstruction can lead to direct cardiac improvements, demonstrated by an increase in LVEDV. Functional annotation of single genetic variants contributing most to the causal effect estimate could help to prioritise biological underpinnings.

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