Detecting and correcting for bias in Mendelian randomization analyses using gene-by-environment interactions

Background: Mendelian randomization has developed into an established method for strengthening causal inference and estimating causal effects, largely due to the proliferation of genome-wide association studies. However, genetic instruments remain controversial as pleiotropic effects can introduce bias into causal estimates. Recent work has highlighted the potential of gene-environment interactions in detecting and correcting for pleiotropic bias in Mendelian randomization analyses. Methods: We introduce MR using Gene-by-Environment interactions (MRGxE) as a framework capable of identifying and correcting for pleiotropic bias, drawing upon developments in econometrics and epidemiology. If an instrument-covariate interaction induces variation in the association between a genetic instrument and exposure, it is possible to identify and correct for pleiotropic effects. The interpretation of MRGxE is similar to conventional summary Mendelian randomization approaches, with a particular advantage of MRGxE being the ability to assess the validity of an individual instrument. Results: We investigate the effect of BMI upon systolic blood pressure (SBP) using data from the UK Biobank and the GIANT consortium using a single instrument (a weighted allelic score). We find MRGxE produces findings in agreement with MR Egger regression in a two-sample summary MR setting, however, association estimates obtained across all methods differ considerably when excluding related participants or individuals of non-European ancestry. This could be a consequence of selection bias, though there is also potential for introducing bias by using a mixed ancestry population. Further, we assess the performance of MRGxE with respect to identifying and correcting for horizontal pleiotropy in a simulation setting, highlighting the utility of the approach even when the MRGxE assumptions are violated. Conclusions: By utilising instrument-covariate interactions within a linear regression framework, it is possible to identify and correct for pleiotropic bias, provided the average magnitude of pleiotropy is constant across interaction covariate subgroups.

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The transferability of lipid loci across African, Asian and European cohorts

Nature Communications ◽

10.1038/s41467-019-12026-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Karoline Kuchenbaecker ◽

◽

Nikita Telkar ◽

Theresa Reiker ◽

Robin G. Walters ◽

...

Keyword(s):

Association Studies ◽

Genetic Risk Score ◽

Genetic Correlations ◽

Serum Levels ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genetic Determinants ◽

Gene Environment ◽

Genome Wide ◽

The Uk

Abstract Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23–0.28, p < 1.9 × 10−14). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions.

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Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

PLoS Medicine ◽

10.1371/journal.pmed.1003553 ◽

2021 ◽

Vol 18 (3) ◽

pp. e1003553

Author(s):

Aaron Leong ◽

Joanne B. Cole ◽

Laura N. Brenner ◽

James B. Meigs ◽

Jose C. Florez ◽

...

Keyword(s):

Odds Ratio ◽

Mendelian Randomization ◽

Association Studies ◽

Statistical Significance ◽

Epidemiological Studies ◽

Population Based ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

The Uk

Background Epidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses. Methods and findings We selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10−8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10−5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10−5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null. Conclusions In this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.

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Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽

10.3390/genes12050772 ◽

2021 ◽

Vol 12 (5) ◽

pp. 772

Author(s):

João Botelho ◽

Vanessa Machado ◽

José João Mendes ◽

Paulo Mascarenhas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

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Association of Physical Activity with Body Composition: A Mendelian Randomization Study

10.31219/osf.io/e3mrx ◽

2021 ◽

Author(s):

Ferris Alaa Ramadan ◽

Katherine Ellingson ◽

Yann Klimentidis

Keyword(s):

Physical Activity ◽

Body Composition ◽

Sedentary Behavior ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Protective Effects ◽

Dietary Interventions ◽

The Uk

Background. Studies suggest that body composition can be improved through physical activity (PA) independently of dietary interventions. A separate line of evidence suggests that PA may reduce high-risk visceral adipose tissue (VAT), without clinically meaningful weight change. Genome-wide association studies have previously identified genetic markers associated with PA behaviors and may provide an opportunity to evaluate hypothesized causal relationships with body composition. Methods. We performed a Mendelian randomization (MR) study to test the incremental benefits of various PA exposures on body composition outcomes as assessed by anthropometric indices, lean body mass (LBM) (kg), body fat (%), and VAT (kg). Genetic instruments were identified for both self-reported and accelerometer-measured PA, including sedentary behavior. Outcomes included anthropometric and dual-energy X-ray absorptiometry measures of adiposity, extracted from the UK Biobank and the largest publicly available consortia. Multivariable MR (MVMR) included educational attainment as a covariate to address potential confounding. Sensitivity analyses were evaluated for weak instrument bias and pleiotropic effects.Results. We did not identify associations between genetically-predicted sedentary behavior (self-reported or accelerometer) and body composition outcomes in MVMR analyses. All analyses for self-reported moderate PA were null for body composition outcomes, including BMI, LBM and VAT. Genetically-predicted PA at higher intensities was protective against VAT in MR and MVMR analyses of both accelerometer-measured vigorous PA (MVMR β = -0.15, 95% Confidence Interval (CI): -0.24, -0.07, p<0.001) and self-reported participation in strenuous sports or other exercises (MVMR β = -0.27, 95%CI: -0.52, -0.01, p=0.034), and was robust across several sensitivity analyses. Conclusions. We did not identify evidence of a causal relationship between genetically-predicted PA and body composition, with the exception of a putatively protective effect of higher-intensity PA on VAT. Protective effects of PA against VAT may support prior evidence of biological pathways through which PA decreases risk of downstream cardiometabolic diseases.

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Growth Differentiation Factor 15 Is Associated With Alzheimer’s Disease Risk

Frontiers in Genetics ◽

10.3389/fgene.2021.700371 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peng-Fei Wu ◽

Xing-Hao Zhang ◽

Ping Zhou ◽

Rui Yin ◽

Xiao-Ting Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

European Ancestry ◽

Reverse Direction ◽

Genome Wide Association Studies ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor

BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10–8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.

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Causal effect of atrial fibrillation/flutter on chronic kidney disease: A bidirectional two-sample Mendelian randomization study

PLoS ONE ◽

10.1371/journal.pone.0261020 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0261020

Author(s):

Masahiro Yoshikawa ◽

Kensuke Asaba ◽

Tomohiro Nakayama

Keyword(s):

Atrial Fibrillation ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Odds Ratio ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

European Population ◽

Genome Wide Association Studies ◽

The Uk

Chronic kidney disease (CKD) and atrial fibrillation are both major burdens on the health care system worldwide. Several observational studies have reported clinical associations between CKD and atrial fibrillation; however, causal relationships between these conditions remain to be elucidated due to possible bias by confounders and reverse causations. Here, we conducted bidirectional two-sample Mendelian randomization analyses using publicly available summary statistics of genome-wide association studies (the CKDGen consortium and the UK Biobank) to investigate causal associations between CKD and atrial fibrillation/flutter in the European population. Our study suggested a causal effect of the risk of atrial fibrillation/flutter on the decrease in serum creatinine-based estimated glomerular filtration rate (eGFR) and revealed a causal effect of the risk of atrial fibrillation/flutter on the risk of CKD (odds ratio, 9.39 per doubling odds ratio of atrial fibrillation/flutter; 95% coefficient interval, 2.39–37.0; P = 0.001), while the causal effect of the decrease in eGFR on the risk of atrial fibrillation/flutter was unlikely. However, careful interpretation and further studies are warranted, as the underlying mechanisms remain unknown. Further, our sample size was relatively small and selection bias was possible.

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High Level of Uromodulin Increases the Risk of Hypertension: A Mendelian Randomization Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.736001 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ruilian You ◽

Lanlan Chen ◽

Lubin Xu ◽

Dingding Zhang ◽

Haitao Li ◽

...

Keyword(s):

Blood Pressure ◽

Causal Relationship ◽

Mendelian Randomization ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Inverse Variance ◽

The Uk ◽

High Level

Background: The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure.Methods: We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis.Results: MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.04 (95% Confidence Interval (CI), 1.03-1.04, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 2.70E-04) in “ieu-b-38” and “ukb-b-20175”, respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, P = 4.38E-06) in “ieu-b-39” and 0.05 (SE = 0.01, P = 2.13E-10) in “ukb-b-7992”. As for the sUMOD, the OR of hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.01 (95% CI 1.01–1.02, all P < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in “ieu-b-38” and 0.01 (SE = 0.003, P = 1.04E-04) in “ukb-b-20175”. The sUMOD is causally associated with elevated DBP (“ieu-b-39”: β = 0.313, SE = 0.050, P = 3.43E-10; “ukb-b-7992”: β = 0.018, SE = 0.003, P = 8.41E-09).Conclusion: Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.

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Causal association of adipokines with osteoarthritis: a Mendelian randomization study

Rheumatology ◽

10.1093/rheumatology/keaa719 ◽

2020 ◽

Author(s):

Jiayao Fan ◽

Jiahao Zhu ◽

Lingling Sun ◽

Yasong Li ◽

Tianle Wang ◽

...

Keyword(s):

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Knee Oa ◽

Genome Wide ◽

A Genome ◽

Weighted Median

Abstract Objective This two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA. Methods Summary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results. Results The positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13–5.09] and weighted median (OR: 2.94, 95% CI: 1.23–6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01–1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18–10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03–1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis. Conclusions An association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

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Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses

BMC Medicine ◽

10.1186/s12916-021-01939-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Maxime M. Bos ◽

Neil J. Goulding ◽

Matthew A. Lee ◽

Amy Hofman ◽

Mariska Bot ◽

...

Keyword(s):

Sleep Duration ◽

Mendelian Randomization ◽

Disease Risk ◽

Association Studies ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Multivariable Regression ◽

Artery Disease ◽

Insomnia Symptoms

Abstract Background Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

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Frequent Daytime Napping is Detrimental to Human Health: A phenotype-wide Mendelian Randomization Study

10.1101/2020.01.20.20017723 ◽

2020 ◽

Author(s):

Lanlan Chen ◽

Aowen Tian ◽

Zhipeng Liu ◽

Miaoran Zhang ◽

Xingchen Pan ◽

...

Keyword(s):

Health Outcomes ◽

Human Health ◽

Mendelian Randomization ◽

Wide Spectrum ◽

Association Studies ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Major Depressive ◽

Genome Wide ◽

The Uk

ABSTRACTBackgroundIt remains controversial whether daytime napping is beneficial for human health.ObjectiveTo examine the causal relationship between daytime napping and the risk for various human diseases.DesignPhenotype-wide Mendelian randomization study.SettingNon-UK Biobank cohorts reported in published genome-wide association studies (GWAS) provided the outcome phenotypes in the discovery stage. The UK Biobank cohort provided the outcome phenotypes in the validation stage.ParticipantsThe UK Biobank GWAS included 361,194 European-ancestry residents in the UK. Non-UKBB GWAS included various numbers of participants.ExposureSelf-reported daytime napping frequency.Main outcome measureA wide-spectrum of human health outcomes including obesity, major depressive disorder, and high cholesterol.MethodsWe examined the causal relationship between daytime napping frequency in the UK Biobank as exposure and a panel of 1,146 health outcomes reported in genome-wide association studies (GWAS), using a two-sample Mendelian randomization analysis. The significant findings were further validated in the UK Biobank health outcomes of 4,203 human traits and diseases. The causal effects were estimated using a fixed-effect inverse variance weighted model. MR-Egger intercept test was applied to detect horizontal pleiotropy, along with Cochran’s Q test to assess heterogeneity among the causal effects of IVs.FindingsThere were significant causal relationships between daytime napping frequency and a wide spectrum of human health outcomes. In particular, we validated that frequent daytime napping increased the risks of major depressive disorder, obesity and abnormal lipid profile.InterpretationThe current study showed that frequent daytime napping mainly had adverse impacts on physical and mental health. Cautions should be taken for health recommendations on daytime napping. Further studies are necessary to precisely define the best daytime napping strategies.

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