Publications
313 results found
Palaniswamy S, Gill D, De Silva NM, et al., 2020, Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study, American Journal of Clinical Nutrition, Vol: 111, Pages: 1036-1047, ISSN: 0002-9165
BackgroundObesity is associated with inflammation but the role of vitamin D in this process is not clear.ObjectivesWe aimed to assess the associations between serum 25-hydroxyvitamin D [25(OH)D], BMI, and 16 inflammatory biomarkers, and to assess the role of vitamin D as a potential mediator in the association between higher BMI and inflammation.MethodsNorthern Finland Birth Cohort 1966 (NFBC1966) 31-y data on 3586 individuals were analyzed to examine the observational associations between BMI, 25(OH)D, and 16 inflammatory biomarkers. Multivariable regression analyses and 2-sample regression-based Mendelian randomization (MR) mediation analysis were performed to assess any role of vitamin D in mediating a causal effect of BMI on inflammatory biomarkers [soluble intercellular adhesion molecule 1 (sICAM-1), high sensitivity C-reactive protein (hs-CRP), and α1-acid glycoprotein (AGP)] for which observational associations were detected. For MR, genome-wide association study summary results ranging from 5163 to 806,834 individuals were used for biomarkers, 25(OH)D, and BMI. Findings were triangulated with a literature review of vitamin D supplementation trials.ResultsIn NFBC1966, mean BMI (kg/m2) was 24.8 (95% CI: 24.7, 25.0) and mean 25(OH)D was 50.3 nmol/L (95% CI: 49.8, 50.7 nmol/L). Inflammatory biomarkers correlated as 4 independent clusters: interleukins, adhesion molecules, acute-phase proteins, and chemokines. BMI was positively associated with 9 inflammatory biomarkers and inversely with 25(OH)D (false discovery rate < 0.05). 25(OH)D was inversely associated with sICAM-1, hs-CRP, and AGP, which were positively associated with BMI. The MR analyses showed causal association of BMI on these 3 inflammatory biomarkers. There was no observational or MR evidence that circulating 25(OH)D concentrations mediated the association between BMI and these 3 inflammatory markers. Review of randomized controlled trials (RCTs) supported our findings showing no impact of
Burgess S, Davey Smith G, Davies NM, et al., 2020, Guidelines for performing Mendelian randomization investigations [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 4, Pages: 1-27, ISSN: 2398-502X
This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months.
Gill D, Arvanitis M, Carter P, et al., 2020, ACE inhibition and cardiometabolic risk factors, lung <i>ACE2</i> and <i>TMPRSS2</i> gene expression, and plasma ACE2 levels: a Mendelian randomization study
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>To use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to provide insight into how these exposures affect lung <jats:italic>ACE2</jats:italic> and <jats:italic>TMPRSS2</jats:italic> gene expression and circulating ACE2 levels.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Two-sample Mendelian randomization (MR) analysis.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>Summary-level genetic association data.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Participants were predominantly of European ancestry. Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants). Genetic association estimates for lung expression of <jats:italic>ACE2</jats:italic> and <jats:italic>TMPRSS2</jats:italic> were obtained from the Gene-Tissue Expression (GTEx) project (515 participants) and the Lung eQTL Consortium (1,038 participants). Genetic association estimates for circulating plasma ACE2 levels were obtained from the INTERVAL study (4,947 participants).</jats:p></jats:sec><jats:sec><jats:title>Main outcomes and measures</jats:title><jats:p>Lung <jats:italic>ACE2</jats:italic> and <jats:italic>TMPRSS2</jats:italic> expression and plasma ACE2 levels.</jats:p></jats:sec><jat
Marini S, Merino J, Montgomery BE, et al., 2020, Mendelian randomization study of obesity and cerebrovascular disease, Annals of Neurology, Vol: 87, Pages: 516-524, ISSN: 0364-5134
OBJECTIVE: To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease. METHODS: We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively. RESULTS: Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose. INTERPRETATION: Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke.
Zuber V, Gill D, Ala-Korpela M, et al., 2020, High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease
<jats:sec><jats:title>Background</jats:title><jats:p>Genetic variants can be used to prioritize risk factors as potential therapeutic targets via Mendelian randomization (MR). An agnostic statistical framework using Bayesian model averaging (MR-BMA) can disentangle the causal role of correlated risk factors with shared genetic predictors. Here, our objective is to identify lipoprotein measures as mediators between lipid-associated genetic variants and coronary artery disease (CAD) for the purpose of detecting therapeutic targets for CAD.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>As risk factors we consider 30 lipoprotein measures and metabolites derived from a high-throughput metabolomics study including 24,925 participants. We fit multivariable MR models of genetic associations with CAD estimated in 453,595 participants (including 113,937 cases) regressed on genetic associations with the risk factors. MR-BMA assigns to each combination of risk factors a model score quantifying how well the genetic associations with CAD are explained. Risk factors are ranked by their marginal score and selected using false discovery rate (FDR) criteria. We perform sensitivity and replication analyses varying the dataset for genetic associations with CAD.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the main analysis, the top combination of risk factors ranked by the model score contains apolipoprotein B (ApoB) only. ApoB is also the highest ranked risk factor with respect to the marginal score (FDR< 0.005). Additionally, ApoB is selected in all replication analyses. No other measure of cholesterol or triglyceride is consistently selected otherwise.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our agnostic genetic investigation prioritizes ApoB across all datasets co
Levin MG, Judy R, Gill D, et al., 2019, Genetics of Height and Risk of Atrial Fibrillation: A Mendelian Randomization Study
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>To determine whether height has a causal effect on risk of atrial fibrillation</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Mendelian randomization study</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>Genome-wide association studies of height and atrial fibrillation; Penn Medicine Biobank</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Multiethnic (predominantly European ancestry) participants in genome-wide association studies of height (693,529 individuals) and atrial fibrillation (65,446 cases and 522,744 controls); 7,023 Penn Medicine Biobank participants of European ancestry</jats:p></jats:sec><jats:sec><jats:title>Exposures</jats:title><jats:p>Height, cardiometabolic risk factors for atrial fibrillation, and randomly allocated genetic variants strongly associated with these traits</jats:p></jats:sec><jats:sec><jats:title>Main outcome measure</jats:title><jats:p>Risk of atrial fibrillation (measured in odds ratio)</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>At the population level, a 1 standard deviation increase in genetically-predicted height was associated with increased odds of AF (Odds ratio [OR] 1.34; 95% Confidence Interval [CI] 1.29 to 1.40; p = 5×10<jats:sup>−42</jats:sup>). These findings remained consistent in sensitivity analyses that were robust to the presence of pleiotropic variants. Results from analyses considering individual-participant data were similar, even after adjustment for clinical covariates, including left atrial size.</jats:p></jats:sec><jats:sec><jats:title>Co
Gill D, Cameron AC, Burgess S, et al., 2019, Urate, blood pressure and cardiovascular disease: updated evidence from Mendelian randomization and meta-analysis of clinical trials
<jats:title>Abstract</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>To investigate the effect of serum urate on blood pressure and cardiovascular disease (CVD) risk by updating evidence from Mendelian randomization (MR) analysis and meta-analysis of randomized controlled trials (RCTs).</jats:p></jats:sec><jats:sec><jats:title>Methods and Results</jats:title><jats:p>Using recently available data from the Million Veterans Program and UK Biobank, the main MR analyses showed that every 1-standard deviation increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio 1.19, 95% confidence interval 1.10-1.30,<jats:italic>P</jats:italic>=4×10<jats:sup>−5</jats:sup>), peripheral artery disease (1.12, 95%CI 1.03 to 1.21,<jats:italic>P</jats:italic>=9×10<jats:sup>−3</jats:sup>), and stroke (1.11, 95%CI 1.05 to 1.18,<jats:italic>P</jats:italic>=2×10<jats:sup>−4</jats:sup>). In MR mediation analyses, SBP was estimated to mediate approximately one third the effect of urate on CVD risk. Systematic review and meta-analysis of RCTs showed a favorable effect of urate-lowering treatment on SBP (mean difference -2.55mmHg, 95%CI -4.06 to -1.05,<jats:italic>P</jats:italic>=1×10<jats:sup>−3</jats:sup>) and major adverse cardiovascular events (MACE) in those with previous CVD (OR 0.40, 95%CI 0.22 to 0.73,<jats:italic>P</jats:italic>=3×10<jats:sup>−3</jats:sup>), but no significant effect on MACE in all individuals (OR 0.73, 95%CI 0.48 to 1.09,<jats:italic>P</jats:italic>=0.12).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>MR and clinical trial data support an effect of higher serum urate on increa
Burgess S, Davey Smith G, Davies N, et al., 2019, Guidelines for performing Mendelian randomization investigations [version 1; peer review: 1 approved, 1 approved with reservations], Wellcome Open Research, Vol: 4, Pages: 1-19, ISSN: 2398-502X
This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months.
Allara E, Morani G, Carter P, et al., 2019, Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled mendelian randomization investigation., Circulation: Genomic and Precision Medicine, Vol: 12, Pages: 543-551, ISSN: 2574-8300
Background - Evidence from randomized trials has shown that therapies that lower low-density lipoprotein (LDL)-cholesterol and triglycerides reduce coronary artery disease (CAD) risk. However, there is still uncertainty regarding their effects on other cardiovascular outcomes. We therefore performed a systematic investigation of causal relationships between circulating lipids and cardiovascular outcomes using a Mendelian randomization approach. Methods - In the primary analysis, we performed two-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188,577 participants, and genetic associations with cardiovascular outcomes from 367,703 participants in UK Biobank. Results - For LDL-cholesterol, in addition to the expected positive associations with CAD risk (odds ratio per 1 standard deviation increase [OR], 1.45; 95% confidence interval [95%CI] 1.35-1.57) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically-predicted LDL-cholesterol with abdominal aortic aneurysm (OR 1.75; 95%CI 1.40-2.17) and aortic valve stenosis (OR 1.46; 95%CI 1.25-1.70). Genetically-predicted triglyceride levels were positively associated with CAD (OR 1.25; 95%CI 1.12-1.40), aortic valve stenosis (OR 1.29; 95%CI 1.04-1.61), and hypertension (OR 1.17; 95%CI 1.07-1.27), but inversely associated with venous thromboembolism (OR 0.79; 95%CI 0.67-0.93) and haemorrhagic stroke (OR 0.78; 95%CI 0.62-0.98). We also found positive associations of genetically-predicted LDL-cholesterol and triglycerides with heart failure that appeared to be mediated by CAD. Co
Gill D, 2019, Heterogeneity between genetic variants as a proxy for pleiotropy in mendelian randomization., JAMA Cardiology, ISSN: 2380-6583
Gill D, Efstathiadou A, Cawood K, et al., 2019, Education protects against coronary heart disease and stroke independently of cognitive function: evidence from Mendelian randomization, International Journal of Epidemiology, Vol: 48, Pages: 1468-1477, ISSN: 0300-5771
Background: There is evidence that education protects against cardiovascular disease. However, it is not known whether such an effect is independent of cognition. Methods: We performed two-sample Mendelian randomization (MR) analyses to investigate the effect of education and cognition respectively, on risk of CHD and ischemic stroke. Additionally, we used multivariable MR to adjust for the effects of cognition and education in the respective analyses to measure the effects of these traits independently of each other.Results: In unadjusted MR, there was evidence that education is causally associated with both CHD and stroke risk (CHD: OR 0.65 per 1-standard deviation [SD, 3.6 years] increase in education; 95% confidence interval [CI] 0.61-0.70, stroke: OR 0.77; 95% CI 0.69-0.86). This effect persisted after adjusting for cognition in multivariable MR (CHD: OR 0.76; 95% CI 0.65-0.89, stroke OR 0.74; 95% CI 0.59-0.92). Cognition had an apparent effect on CHD risk in unadjusted MR (OR per 1-SD increase 0.80; 95% CI 0.74-0.85), however after adjusting for education this was no longer observed (OR 1.03; 95% CI 0.86-1.25). Cognition did not have any notable effect on the risk of developing ischemic stroke, with (OR 0.97; 95% CI 0.87-1.08) or without adjustment for education (OR 1.04; 95% CI 0.79-1.36).Conclusion: This study provides evidence to support that education protects against CHD and ischemic stroke risk independently of cognition, but does not provide evidence to support that cognition protects against CHD and stroke risk independently of education. These findings could have implications for education and health policy.
Georgakis MK, Malik R, Gill D, et al., 2019, Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Studies in humans and experimental models highlight a role of interleukin-6 (IL-6) in cardiovascular disease. Indirect evidence suggests that inhibition of IL-6 signaling could lower risk of coronary artery disease. However, whether such an approach would be effective for ischemic stroke and other cardiovascular outcomes remains unknown.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In a genome-wide association study (GWAS) of 204,402 European individuals, we identified genetic proxies for downregulated IL-6 signaling as genetic variants in the IL-6 receptor (<jats:italic>IL6R</jats:italic>) locus that were associated with lower C-reactive protein (CRP) levels, a downstream effector of IL-6 signaling. We then applied two-sample Mendelian randomization (MR) to explore associations with ischemic stroke and its major subtypes (large artery stroke, cardioembolic stroke, small vessel stroke) in the MEGASTROKE dataset (34,217 cases and 404,630 controls), with coronary artery disease in the CARDIoGRAMplusC4D dataset (60,801 cases and 123,504 control), and with other cardiovascular outcomes in the UK Biobank (up to 321,406 individuals) and in phenotype-specific GWAS datasets. All effect estimates were scaled to the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified 7 genetic variants as proxies for downregulated IL-6 signaling, which showed effects on upstream regulators (IL-6 and soluble IL-6R levels) and downstream effectors (CRP and fibrinogen levels) of the pathway that were consistent with pharmacological blockade of IL-6R. In MR, proxies for downregulated IL-6 signaling were associated with lower risk of ischemic stroke (Odds Ratio [OR
Charani E, DeBarra E, Gill D, et al., 2019, Antibiotic prescribing in general medical and surgical specialties: a prospective cohort study, Antimicrobial Resistance and Infection Control, Vol: 8, Pages: 1-10, ISSN: 2047-2994
Background: Qualitative work has described the differences in prescribing practice across medical and surgical specialties. This study aimed to understand if specialty impacts quantitative measures of prescribing practice. Methods: We prospectively analysed the antibiotic prescribing across general medical and surgical teams for acutely admitted patients. Over a 12-month period (June 2016 – May 2017) 659 patients (362 medical, 297 surgical) were followed for the duration of their hospital stay. Antibiotic prescribing across these cohorts was assessed using Chi-squared or Wilcoxon rank-sum, depending on normality of data. The t-test was used to compare age and length of stay. A logistic regression model was used to predict escalation of antibiotic therapy. Results: Surgical patients were younger (p<0.001) with lower Charlson Comorbidity Index scores (p<0.001). Antibiotics were prescribed for 45% (162/362) medical and 55% (164/297) surgical patients. Microbiological results were available for 26% (42/164) medical and 29% (48/162) surgical patients, of which 55% (23/42) and 48% (23/48) were positive respectively. There was no difference in the spectrum of antibiotics prescribed between surgery and medicine (p=0.507). In surgery antibiotics were 1) prescribed more frequently (p=0.001); 2) for longer (p=0.016); 3) more likely to be escalated (p=0.004); 4) less likely to be compliant with local policy (p<0.001) than medicine. Conclusions: Across both specialties, microbiology investigation results are not adequately used to diagnose infections and optimise their management. There is significant variation in antibiotic decision-making (including escalation patterns) between general surgical and medical teams. Antibiotic stewardship interventions targeting surgical specialties need to go beyond surgical prophylaxis. It is critical to focus on of review the patients initiated on therapeutic antibiotics in surgical specialties to ensure that escalation and c
Efstathiadou A, Gill D, McGrane F, et al., 2019, Genetically determined uric acid and the risk of cardiovascular and neurovascular diseases: a mendelian randomization study of outcomes investigated in randomized trials., Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease, Vol: 8, Pages: 1-55, ISSN: 2047-9980
Background Higher serum uric acid levels are associated with cardiovascular and neurovascular disease, but whether these relationships are causal is not known. We applied Mendelian randomization approaches to assess the association between genetically determined uric acid levels and outcomes under study in large clinical trials. Methods and Results We used 28 genetic variants related to serum uric acid as instruments to perform a range of 2-sample Mendelian randomization methods. Our analysis had statistical power to detect clinically relevant effects of genetically determined serum uric acid levels on the considered clinical outcomes; cognitive function, Alzheimer disease, coronary heart disease, myocardial infarction, systolic blood pressure, and stroke. There was some suggestive evidence for an association between higher genetically determined serum uric acid and cognitive function. There was also some suggestive evidence of a relationship between coronary heart disease, systolic blood pressure, and the serum uric acid genetic instruments, but likely related to genetic pleiotropy. Overall, there was no consistent evidence of a clinically relevant effect of genetically determined serum uric acid on any of the considered outcomes. Conclusions This Mendelian randomization study does not support a clinically relevant causal effect of genetically determined serum urate on a range of cardiovascular and neurovascular outcomes. The weak association of genetically determined serum urate with coronary heart disease and systolic blood pressure may be because of pleiotropic effects. If urate lowering drugs such as allopurinol are found to affect these outcomes in clinical trials, then the effects may be mediated through urate independent mechanisms.
Carter A, Gill D, Davies N, et al., 2019, WHAT EXPLAINS THE EFFECT OF EDUCATION ON CARDIOVASCULAR DISEASE? APPLYING MENDELIAN RANDOMISATION TO IDENTIFY THE CONSEQUENCES OF EDUCATION INEQUALITY, Publisher: BMJ PUBLISHING GROUP, Pages: A8-A9, ISSN: 0143-005X
Pazoki R, Evangelou E, Mosen-Ansorena D, et al., 2019, GWAS for urinary sodium and potassium excretion highlights pathways shared with cardiovascular traits, Nature Communications, Vol: 10, ISSN: 2041-1723
Urinary sodium and potassium excretion are associated with blood pressure (BP) and cardiovascular disease (CVD). The exact biological link between these traits is yet to be elucidated. Here, we identify 51 loci for sodium and 13 for potassium excretion in a large-scale genome-wide association study (GWAS) on urinary sodium and potassium excretion using data from 446,237 individuals of European descent from the UK Biobank study. We extensively interrogate the results using multiple analyses such as Mendelian randomization, functional assessment, co localization, genetic risk score, and pathway analyses. We identify a shared genetic component between urinary sodium and potassium expression and cardiovascular traits. Ingenuity pathway analysis shows that urinary sodium and potassium excretion loci are over represented in behavioural response to stimuli. Our study highlights pathways that are shared between urinary sodium and potassium excretion and cardiovascular traits.
Gill D, Brewer CF, Monori G, et al., 2019, The effect of genetically determined iron status on risk of venous thromboembolism and carotid atherosclerotic disease: A Mendelian randomization study, Journal of the American Heart Association, Vol: 8, ISSN: 2047-9980
Background: Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this work was to investigate the effect of genetically determined iron status on carotid intima-media thickness (cIMT), carotid plaque and venous thromboembolism (VTE) using Mendelian randomization (MR). Methods and Results: Genetic instrumental variables for iron status were selected from a genome-wide meta-analysis of 48,972 subjects. Genetic association estimates for cIMT and carotid plaque were obtained using data from 71,128 and 48,434 participants respectively, whilst estimates for VTE were obtained using data from a study incorporating 7,507 cases and 52,632 controls. Conventional two-sample summary data MR was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of VTE. Odds ratios (ORs) per standard deviation increase in biomarker levels were 1.37 (95% confidence interval 1.14–1.66) for serum iron, 1.25 (1.09–1.43) for transferrin saturation, 1.92 (1.28–2.88) for ferritin, and 0.76 (0.63–0.92) for serum transferrin (with higher transferrin levels representing lower iron status). In contrast, higher iron status was associated with lower risk of carotid plaque. Corresponding ORs were 0.85 (0.73-0.99) for serum iron and 0.89 (0.80–1.00) for transferrin saturation, with concordant trends for serum transferrin and ferritin that did not reach statistical significance. There was no MR evidence of an effect of iron status on cIMT. Conclusions: These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease, but increases risk of thrombosis related to stasis of blood.
Gill D, James NE, Monori G, et al., 2019, Genetically determined risk of depression and functional outcome after ischemic stroke, Stroke, Vol: 50, Pages: 2219-2222, ISSN: 0039-2499
Background and Purpose- Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depression on these outcomes using the Mendelian randomization (MR) framework. Methods- Genetic instruments for risk of depression were identified in a discovery genome-wide association study of 246 363 cases and 561 190 controls and further replicated in a separate population of 474 574 cases and 1 032 579 controls. Corresponding genetic association estimates for risk of ischemic stroke were taken from 60 341 cases and 454 450 controls, with those for functional outcome 3 months after ischemic stroke taken from an analysis of 6021 patients. Following statistical power calculation, inverse-variance weighted MR was performed to pool estimates across different instruments. The Cochran Q heterogeneity test, weighted median MR, and MR pleiotropy residual sum and outlier were used to explore possible bias relating to inclusion of pleiotropic variants. Results- There was no MR evidence for an effect of genetically determined risk of depression on ischemic stroke risk. Although suffering low statistical power, the main inverse-variance weighted MR analysis was suggestive of a detrimental effect of genetically determined risk of depression on functional outcome after ischemic stroke (odds ratio of poor outcome [modified Rankin Scale, ≥3] per 1-SD increase in genetically determined risk of depression, 1.81; 95% CI, 0.98-3.35; P=0.06). There was no evidence of heterogeneity between MR estimates produced by different instruments (Q P=0.26). Comparable MR estimates were obtained with weighted median MR (odds ratio, 2.57; 95% CI, 1.05-6.25; P=0.04) and MR pleiotropy residual sum and outlier (odds ratio, 1.81; 95% CI, 0.95-3.46; P=0.08). Conclusions- We found no MR evidence of genetically determined risk of depression affecting ischemic stroke risk but did find consistent MR evidence suggestive of a possi
Gill D, Georgakis MK, Koskeridis F, et al., 2019, Use of genetic variants related to antihypertensive drugs to inform on efficacy and side effects, Circulation, Vol: 140, Pages: 270-279, ISSN: 0009-7322
Background: Drug effects can be investigated through natural variation in the genes for their protein targets. The current study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are amongst the most commonly used medications worldwide. Methods: Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure (SBP) at genome-wide significance. Mendelian randomization (MR) estimates for drug effects on coronary heart disease (CHD) and stroke risk were compared to randomized controlled trial (RCT) results. Phenome-wide association study (PheWAS) in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University Biobank (BioVU) and in observational analysis of the UK Biobank.Results: Suitable genetic proxies for angiotensin-converting-enzyme inhibitors (ACEIs), beta-blockers (BBs) and calcium channel blockers (CCBs) were identified. MR estimates for their effect on CHD and stroke risk respectively were comparable to results from RCTs against placebo. PheWAS in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio [OR] 1.02 per standard deviation increase, 95%CI 1.01-1.04), with a consistent estimate found in BioVU (OR 1.01, 95%CI 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to non-dihydropyridine CCBs (hazard ratio [HR] 1.49 considering thiazide diuretics as a comparator, 95%CI 1.04-2.14), but not dihydropyridine CCBs (HR 1.04, 95%CI 0.83-1.32). Conclusions: Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of non-dihydropyridine CCBs on diverticulosis risk could have cli
Pazoki R, Evangelou E, Mosen-Ansorena D, et al., 2019, PATHWAYS UNDERLYING URINARY SODIUM AND POTASSIUM EXCRETION AND THE LINK TO BLOOD PRESSURE AND CARDIOVASCULAR DISEASE, Journal of Hypertension, Vol: 37, Pages: e74-e74, ISSN: 0263-6352
Gill D, Benyamin B, Moore LSP, et al., 2019, Associations of genetically determined iron status across the phenome: a mendelian randomization study, PLoS Medicine, Vol: 16, ISSN: 1549-1277
BackgroundIron is integral to many physiological processes and variations in its levels, even within the normal range, can have implications for health. The objective of this study was to explore the broad clinical effects of varying iron status.Methods and FindingsGenome-wide association study summary data obtained from 48,972 European individuals (55% female) across 19 cohorts in the Genetics of Iron Status Consortium were used to identify three genetic variants (rs1800562 and rs1799945 in the hemochromatosis gene, and rs855791 in the transmembrane protease serine 6 gene) that associate with increased serum iron, ferritin and transferrin saturation, and decreased transferrin levels, thus serving as instruments for systemic iron status. Phenome-wide association study (PheWAS) of these instruments was performed on 415,482 European individuals (54% female) in the UK Biobank that were aged 40-69 years when recruited from 2006 to 2010, with their genetic data linked to Hospital Episode Statistics from April 1995 to March 2016. Two-sample summary data Mendelian randomization (MR) analysis was performed to investigate the effect of varying iron status on outcomes across the human phenome. MR-PheWAS analysis for the three iron status genetic instruments was performed separately and then pooled by meta-analysis. Correction was made for testing of multiple correlated phenotypes using a 5% false discovery rate threshold. Heterogeneity between MR estimates for different instruments was used to indicate possible bias due to effects of the genetic variants through pathways unrelated to iron status. There were 904 distinct phenotypes included in the MR-PheWAS analyses. After correcting for multiple testing, the three genetic instruments for systemic iron status demonstrated consistent evidence of a causal effect of higher iron status on decreasing risk of traits related to anemia (iron deficiency anemia: odds ratio [OR] scaled to a standard deviation increase in genetically dete
Allara E, Morani G, Carter P, et al., 2019, Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>To systematically investigate causal relationships between circulating lipids and cardiovascular outcomes, using a Mendelian randomization approach.</jats:p></jats:sec><jats:sec><jats:title>Methods and Results</jats:title><jats:p>In the primary analysis, we performed two-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188,577 participants, and genetic associations with cardiovascular outcomes from 367,703 participants in UK Biobank.</jats:p><jats:p>For LDL-cholesterol, in addition to the expected positive associations with coronary artery disease (CAD) risk (odds ratio per 1 standard deviation increase [OR], 1.45; 95% confidence interval [95%CI] 1.35-1.57) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically-predicted LDL-cholesterol with abdominal aortic aneurysm (OR 1.75; 95%CI 1.40-2.17), and aortic valve stenosis (OR 1.46; 95%CI 1.25-1.70). Genetically-predicted triglyceride levels were positively associated with CAD (OR 1.25; 95%CI 1.12-1.40), aortic valve stenosis (OR 1.29; 95%CI 1.04-1.61), and hypertension (OR 1.17; 95%CI 1.07-1.27), but inversely associated with venous thromboembolism (OR 0.79; 95%CI 0.67-0.93). The positive associations of genetically-predicted LDL-cholesterol and triglycerides with heart failure and aortic stenosis appeared to be mediated by CAD.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</
Dimou N, Papadimitriou N, Gill D, et al., 2019, Sex hormone binding globulin and risk of breast cancer: a Mendelian randomization study, International Journal of Epidemiology, Vol: 48, Pages: 807-816, ISSN: 1464-3685
BackgroundThere are observational data suggesting an inverse association between circulating concentrations of sex hormone binding globulin (SHBG) and risk of postmenopausal breast cancer. However, causality is uncertain and few studies have investigated this association by tumour receptor status. We aimed to investigate these associations under the causal framework of Mendelian randomization (MR).MethodsWe used summary association estimates extracted from published genome-wide association study (GWAS) meta-analyses for SHBG and breast cancer, to perform two-sample MR analyses. Summary statistics were available for 122 977 overall breast cancer cases, of which 69 501 were estrogen receptor positive (ER+ve) and 21 468 were ER-ve, and 105 974 controls. To control for potential horizontal pleiotropy acting via body mass index (BMI), we performed multivariable inverse-variance weighted (IVW) MR as the main analysis, with the robustness of this approach further tested in sensitivity analyses.ResultsThe multivariable IVW MR analysis indicated a lower risk of overall (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.90, 0.98; P: 0.006) and ER+ve (OR: 0.92; 95% CI: 0.87, 0.97; P: 0.003) breast cancer, and a higher risk of ER-ve disease (OR: 1.09; 95% CI: 1.00, 1.18; P: 0.047) per 25 nmol/L higher SHBG levels. Sensitivity analyses were consistent with the findings of the main analysis.ConclusionsWe corroborated the previous literature evidence coming from observational studies for a potentially causal inverse association between SHBG concentrations and risk of ER+ve breast cancer, but our findings also suggested a potential novel positive association with ER-ve disease that warrants further investigation, given the low prior probability of being true.
Carter AR, Gill D, Davies NM, et al., 2019, Understanding the consequences of education inequality on cardiovascular disease: mendelian randomisation study, BMJ, Vol: 365, ISSN: 0959-8138
OBJECTIVES: To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes. DESIGN: Mendelian randomisation study. SETTING: UK Biobank and international genome-wide association study data. PARTICIPANTS: Predominantly participants of European ancestry. EXPOSURE: Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation. MAIN OUTCOMES MEASURE: The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively. RESULTS: Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63, 0.60 to 0.67) in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15% (95% confidence interval 13% to 17%) and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease. CONCLUSIONS: BMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the ris
de Vries PS, Sabater-Lleal M, Huffman JE, et al., 2019, A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology, Blood, Vol: 133, Pages: 967-977, ISSN: 0006-4971
Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.
Georgakis MK, Gill D, Rannikmaee K, et al., 2019, Genetically Determined Levels of Circulating Cytokines and Risk of Stroke: Role of Monocyte Chemoattractant Protein-1, CIRCULATION, Vol: 139, Pages: 256-268, ISSN: 0009-7322
Maners J, Gill D, Pankratz N, et al., 2019, Genetically Determined Fibrinogen, Gamma Prime Fibrinogen and Risk of Venous Thromboembolism and Ischemic Stroke: Evidence From Mendelian Randomization, Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Lifestyle and Cardiometabolic Health, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
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Carter AR, Gill D, Davies NM, et al., 2018, What explains the effect of education on cardiovascular disease? Applying Mendelian randomization to identify the consequences of education inequality
<jats:title>Key Points</jats:title><jats:sec><jats:title>Question</jats:title><jats:p>What is the role of body mass index, systolic blood pressure and smoking in mediating the effect of education on cardiovascular disease risk?</jats:p></jats:sec><jats:sec><jats:title>Finding</jats:title><jats:p>We find consistent evidence that body mass index, systolic blood pressure and smoking mediate the effect of education, explaining up to 18%, 27% and 33% respectively. Including all three risk factors in a model together explains around 40% of the effect of education.</jats:p></jats:sec><jats:sec><jats:title>Meaning</jats:title><jats:p>Intervening on body mass index, systolic blood pressure and smoking would lead to reductions in cases of CVD attributable to lower levels of education. Over half of the effect of education on risk of cardiovascular disease is not mediated through these risk factors.</jats:p></jats:sec><jats:sec><jats:title>Importance</jats:title><jats:p>Lower levels of education are causally related to higher cardiovascular risk, but the extent to which this is driven by modifiable risk factors also associated with education is unknown.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To investigate the role of body mass index, systolic blood pressure and smoking in explaining the effect of education on risk of cardiovascular disease outcomes.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Multivariable regression analysis of observational data and Mendelian randomization (MR) analysis of genetic data.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>UK Biobank and international genome-wide association study consortia.</jats:p></jats:sec>&l
Gill D, Monori G, Georgakis MK, et al., 2018, Genetically determined platelet count and risk of cardiovascular disease: Mendelian randomization study, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol: 38, Pages: 2862-2869, ISSN: 1079-5642
Objective—Cardiovascular disease, including coronary artery disease (CAD) and ischemic stroke, is the leading cause of death worldwide. This Mendelian randomization study uses genetic variants as instruments to investigate whether there is a causal effect of genetically determined platelet count on CAD and ischemic stroke risk.Approach and Results—A genome-wide association study of 166 066 subjects was used to identify instruments and genetic association estimates for platelet count. Genetic association estimates for CAD and ischemic stroke were obtained from genome-wide association studies, including 60 801 CAD cases and 123 504 controls, and 60 341 ischemic stroke cases and 454 450 controls, respectively. The inverse-variance weighted meta-analysis of ratio method Mendelian randomization estimates was the main method used to obtain estimates for the causal effect of genetically determined platelet count on risk of cardiovascular outcomes. We found no significant Mendelian randomization effect of genetically determined platelet count on risk of CAD (odds ratio of CAD per SD unit increase in genetically determined platelet count, 1.01; 95% CI, 0.98–1.04; P=0.60). However, higher genetically determined platelet count was causally associated with an increased risk of ischemic stroke (odds ratio, 1.07; 95% CI, 1.04–1.11; P<1×10−5), including all major ischemic stroke subtypes. Similar results were obtained in sensitivity analyses more robust to the inclusion of pleiotropic genetic variants.Conclusions—This Mendelian randomization study found evidence that higher genetically determined platelet count is causally associated with higher risk of ischemic stroke.
Gill D, Monori G, Tzoulaki I, et al., 2018, Iron status and risk of stroke, Stroke, Vol: 49, Pages: 2815-2821, ISSN: 0039-2499
Background and Purpose- Both iron deficiency and excess have been associated with stroke risk in observational studies. However, such associations may be attributable to confounding from environmental factors. This study uses the Mendelian randomization technique to overcome these limitations by investigating the association between genetic variants related to iron status and stroke risk. Methods- A study of 48 972 subjects performed by the Genetics of Iron Status consortium identified genetic variants with concordant relations to 4 biomarkers of iron status (serum iron, transferrin saturation, ferritin, and transferrin) that supported their use as instruments for overall iron status. Genetic estimates from the MEGASTROKE consortium were used to investigate the association between the same genetic variants and stroke risk. The 2-sample ratio method Mendelian randomization approach was used for the main analysis, with the MR-Egger and weighted median techniques used in sensitivity analyses. Results- The main results, reported as odds ratio (OR) of stroke per SD unit increase in genetically determined iron status biomarker, showed a detrimental effect of increased iron status on stroke risk (serum iron OR, 1.07; 95% CI, 1.01-1.14; [log-transformed] ferritin OR, 1.18; 95% CI, 1.02-1.36; and transferrin saturation OR, 1.06; 95% CI, 1.01-1.11). A higher transferrin, indicative of lower iron status, was also associated with decreased stroke risk (OR, 0.92; 95% CI, 0.86-0.99). Examining ischemic stroke subtypes, we found the detrimental effect of iron status to be driven by cardioembolic stroke. These results were supported in statistical sensitivity analyses more robust to the inclusion of pleiotropic variants. Conclusions- This study provides Mendelian randomization evidence that higher iron status is associated with increased stroke risk and, in particular, cardioembolic stroke. Further work is required to investigate the underlying mechanism and whether this can
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