Publications
312 results found
Cameron A, Doherty D, Abdul-Rahim AH, et al., 2020, URATE LOWERING AND CARDIOVASCULAR DISEASE: AN UPDATED SYSTEMATIC REVIEW AND META-ANALYSIS, Publisher: SAGE PUBLICATIONS LTD, Pages: 164-164, ISSN: 1747-4930
Karhunen V, Gill D, Malik R, et al., 2020, Genetic study of circulating cytokines offers insight into the determinants, cascades and effects of systemic inflammation
<jats:title>Abstract</jats:title><jats:p>Cytokines are the signalling molecules that underlie inflammatory processes. Here, we performed genome-wide association study (GWAS) analyses of 47 circulating cytokines in up to 13,365 individuals to identify protein quantitative trait loci (pQTL). Applying a novel approach, we incorporated pQTL and expression quantitative trait loci (eQTL) data of 10,361 tissue samples in 635 individuals to identify biologically plausible genetic instruments to proxy the effect of cytokines. Using Mendelian randomization analysis, we explored the causal determinants of inflammatory cytokines, investigated inflammatory cascades and evaluated their effects on 20 diseases. We show evidence of body mass index (BMI), smoking and systolic blood pressure (SBP) being associated with inflammation, and specifically BMI affecting levels of active PAI-1, HGF, MCP1, sE-Selectin, sICAM1, TRAIL, IL6 and CRP. Our analysis highlights a key role of VEGF in influencing the levels of eight other inflammatory cytokines. Finally, we report evidence of sICAM affecting waist circumference and risk of major depressive disorder, evidence for TRAIL affecting the risk of cardiovascular diseases, breast and prostate cancer, and evidence for MIG affecting the risk of stroke. Overall, our results offer insight into inflammatory mediators of BMI, smoking and SBP, pleiotropic effects of VEGF, and circulating cytokines that increase the risk of cancer, cardiovascular, metabolic and neuropsychiatric diseases. All the studied cytokines represent pharmacological targets and therefore offer opportunities for clinical translation in diseases with inflammatory components.</jats:p>
Levin MG, Judy R, Gill D, et al., 2020, Genetics of height and risk of atrial fibrillation: A Mendelian randomization study, PLoS Medicine, Vol: 17, Pages: 1-17, ISSN: 1549-1277
BackgroundObservational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.Methods and findingsIn summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10−42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55–72; 38% female; recruitment 2008–2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.ConclusionsIn this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthro
Gill D, Burgess S, 2020, Use of a genetic variant related to circulating factor Xa levels to proxy the effect of factor Xa Inhibition on cardiovascular outcomes, Circulation: Genomic and Precision Medicine, Vol: 13, Pages: 551-553, ISSN: 2574-8300
Gill D, 2020, Letter by gill regarding article, "white blood cells and blood pressure: a mendelian randomization study"., Circulation, Vol: 142, Pages: e187-e188, ISSN: 0009-7322
Markozannes G, Koutsioumpa C, Cividini S, et al., 2020, Global assessment of C-reactive protein and health-related outcomes: an umbrella review of evidence from observational studies and Mendelian randomization studies, European Journal of Epidemiology, Vol: 36, Pages: 11-36, ISSN: 0393-2990
C-reactive protein (CRP) has been studied extensively for association with a large number of non-infectious diseases and outcomes. We aimed to evaluate the breadth and validity of associations between CRP and non-infectious, chronic health outcomes and biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses and a systematic review of Mendelian randomization (MR) studies. PubMed, Scopus, and Cochrane Database of Systematic Reviews were systematically searched from inception up to March 2019. Meta-analyses of observational studies and MR studies examining associations between CRP and health outcomes were identified, excluding studies on the diagnostic value of CRP for infections. We found 113 meta-analytic comparisons of observational studies and 196 MR analyses, covering a wide range of outcomes. The overwhelming majority of the meta-analyses of observational studies reported a nominally statistically significant result (95/113, 84.1%); however, the majority of the meta-analyses displayed substantial heterogeneity (47.8%), small study effects (39.8%) or excess significance (41.6%). Only two outcomes, cardiovascular mortality and venous thromboembolism, showed convincing evidence of association with CRP levels. When examining the MR literature, we found MR studies for 53/113 outcomes examined in the observational study meta-analyses but substantial support for a causal association with CRP was not observed for any phenotype. Despite the striking amount of research on CRP, convincing evidence for associations and causal effects is remarkably limited.
Mark PJ, Gkatzionis A, Walker V, et al., 2020, Cardiometabolic traits, sepsis and severe covid-19 with respiratory failure: a Mendelian randomization investigation, Circulation, Vol: 142, Pages: 1791-1793, ISSN: 0009-7322
Objectives: To investigate whether there is a causal effect of cardiometabolic traits on risk of sepsis and severe covid-19.Design: Mendelian randomisation analysis.Setting: UK Biobank and HUNT study population-based cohorts for risk of sepsis, and genome-wide association study summary data for risk of severe covid-19 with respiratory failure.Participants: 12,455 sepsis cases (519,885 controls) and 1,610 severe covid-19 with respiratory failure cases (2,205 controls).Exposure: Genetic variants that proxy body mass index (BMI), lipid traits, systolic blood pressure, lifetime smoking score, and type 2 diabetes liability - derived from studies considering between 188,577 to 898,130 participants. Main outcome measures: Risk of sepsis and severe covid-19 with respiratory failure.Results: Higher genetically proxied BMI and lifetime smoking score were associated with increased risk of sepsis in both UK Biobank (BMI: odds ratio 1.38 per standard deviation increase, 95% confidence interval [CI] 1.27 to 1.51; smoking: odds ratio 2.81 per standard deviation increase, 95% CI 2.09-3.79) and HUNT (BMI: 1.41, 95% CI 1.18 to 1.69; smoking: 1.93, 95% CI 1.02-3.64). Higher genetically proxied BMI and lifetime smoking score were also associated with increased risk of severe covid-19, although with wider confidence intervals (BMI: 1.75, 95% CI 1.20 to 2.57; smoking: 3.94, 95% CI 1.13 to 13.75). There was limited evidence to support associations of genetically proxied lipid traits, systolic blood pressure or type 2 diabetes liability with risk of sepsis or severe covid-19. Similar findings were generally obtained when using Mendelian randomization methods that are more robust to the inclusion of pleiotropic variants, although the precision of estimates was reduced.Conclusions: Our findings support a causal effect of elevated BMI and smoking on risk of sepsis and severe covid-19. Clinical and public health interventions targeting obesity and smoking are likely to reduce sepsis and covid
Burgess S, O'Donnell CJ, Gill D, 2020, Expressing results from a mendelian randomization analysis: separating results from inferences., JAMA Cardiology, Vol: 6, Pages: 7-8, ISSN: 2380-6583
Larsson SC, Burgess S, Gill D, 2020, Genetically proxied inhibition of interleukin-6 signaling: opposing associations with susceptibility to COVID-19 and pneumonia
<jats:title>ABSTRACT</jats:title><jats:p>The inflammatory cytokine interleukin-6 (IL-6) is pivotal for orchestrating the immune response. Inhibitors of IL-6 signaling are being investigated as treatments for severe coronavirus disease 2019 (COVID-19). We conducted a Mendelian randomization study investigating the effect of IL-6 signaling on susceptibility to COVID-19 and pneumonia. Our results showed that genetically proxied inhibition of IL-6 signaling was associated with reduced risk of COVID-19, but also with increased risk of pneumonia. Respiratory disease is a main feature of severe COVID-19, and the potential of IL-6 signaling inhibitors to increase risk of pneumonia warrants vigilance and caution in their application to treat COVID-19.</jats:p>
Burgess S, Gill D, 2020, Rising numbers of positive covid-19 tests in the UK., BMJ, Vol: 370, Pages: m3605-m3605, ISSN: 1759-2151
Jones DP, Wootton RE, Gill D, et al., 2020, Mental health as a mediator of the association between educational inequality and cardiovascular disease: A Mendelian randomisation study
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Education is inversely associated with cardiovascular disease. Several mediators for this association have been established but a significant proportion of the protective effect remains unaccounted for. Mental health is a proposed mediator, but current evidence is mixed and subject to bias from confounding factors and reverse causation. Mendelian randomisation (MR) is an instrumental variable technique that uses genetic proxies for exposures and mediators to reduce such bias.</jats:p></jats:sec><jats:sec><jats:title>Methods and Results</jats:title><jats:p>We used logistic regression and two-step MR analyses to investigate whether educational attainment affects risk of mental health disorders. We then performed observational and MR mediation analyses to explore whether mental health disorders mediate the association between educational attainment and risk of cardiovascular disease. Higher levels of educational attainment were associated with reduced depression, anxiety and cardiovascular disease in observational analyses [Odds Ratio (95% Confidence interval) 0.79 (0.77-0.81), 0.76 (0.73-0.79) and 0.79 (0.78-0.81) respectively], and MR analyses provided support for these reflecting causal effects [OR (95% CI) 0.72 (0.67-0.77), 0.50 (0.42-0.59) and 0.62 (0.58-0.66) respectively]. Both anxiety and depression were associated with cardiovascular disease in observational analyses [OR (95% CI) 1.63 (1.49-1.79) and OR (95% CI) 1.70 (1.59-1.82) respectively] but only depression was associated in the MR analyses [OR (95% CI) 1.09 (1.03-1.15)]. Roughly 6% of the total protective effect of education on cardiovascular disease was mediated by depression.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Higher levels of educational attainment protect against mental he
Rogne T, Liyanarachi KV, Rasheed H, et al., 2020, Genome-wide association study of skin and soft tissue infection susceptibility
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Skin and soft tissue infections (SSTIs) are common worldwide, but little is known about the genetic susceptibility and the causal effect of cardiometabolic risk factors. We therefore conducted the first genome-wide association study (GWAS) of SSTIs, with downstream analyses including Mendelian randomization analyses.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The GWAS was conducted using the UK Biobank as discovery cohort, with 6,107 cases and 399,239 controls, and the Trøndelag Health Study (HUNT) as replication cohort with 1,657 cases and 67,522 controls. Cases and controls were those who had or had not been hospitalized with an SSTI diagnosis, respectively.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>One locus, lead single-nucleotide polymorphism rs3749748 in <jats:italic>LINC01184/SLC12A2</jats:italic>, was associated with SSTIs in the UK Biobank (odds ratio [OR] 1.19, p-value = 7.6e-16) and replicated in HUNT (OR 1.15, p-value = 6.3e-4). Meta-analysis confirmed the lead variant (OR 1.18, p-value = 4.4e-18), as well as suggested two additional loci close to genome-wide significance (rs2007361 in <jats:italic>PSMA1</jats:italic>, OR 0.91, p-value = 5.1e-8; and rs78625038 in <jats:italic>GAN</jats:italic>, OR 1.86, p-value = 5.9e-8). Gene-based association tests identified four genes linked to SSTIs: <jats:italic>SLC12A2, PSMA1, GAN</jats:italic>, and <jats:italic>IL6R</jats:italic>. The minor allele of rs3749748 reduced the gene expression of <jats:italic>SLC12A2</jats:italic> primarily in monocytes and macrophages. Mendelian randomization analyses showed that increasing body mass index and lifetime smoking habits increased risk of SSTIs.</j
Burgess S, Ponsford MJ, Gill D, 2020, Are we underestimating seroprevalence of SARS-CoV-2? Current antibody tests fail to identify people who had mild infections, BMJ-BRITISH MEDICAL JOURNAL, Vol: 370, ISSN: 0959-535X
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- Citations: 42
Gill D, 2020, Leverage of genetic variants proxying smoking intensity to explore the broad health consequences of smoking, EClinicalMedicine, Vol: 26, Pages: 100498-100498, ISSN: 2589-5370
Levin MG, Klarin D, Walker VM, et al., 2020, Genetic Variation in Blood Pressure and Lifetime Risk of Peripheral Artery Disease: A Mendelian Randomization Study
<jats:title>ABSTRACT:</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>We aimed to estimate the effect of blood pressure and blood pressure lowering medications (via genetic proxies) on peripheral artery disease.</jats:p></jats:sec><jats:sec><jats:title>Methods and Results</jats:title><jats:p>GWAS summary statistics were obtained for BP (International Consortium for Blood Pressure + UK Biobank GWAS; N = up to 757,601 individuals), peripheral artery disease (PAD; VA Million Veteran Program; N = 24,009 cases, 150,983 controls), and coronary artery disease (CAD; CARDIoGRAMplusC4D 1000 Genomes; N = 60,801 cases, 123,504 controls). Genetic correlations between systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP) and CAD and PAD were estimated using LD score regression. The strongest correlation was between SBP and CAD (r<jats:sub>g</jats:sub>= 0.36; p = 3.9 × 10<jats:sup>−18</jats:sup>). Causal effects were estimated by two-sample MR using a range of pleiotropy-robust methods. Increased SBP, DBP, and PP increased risk of both PAD (SBP OR 1.25 [1.19–1.31] per 10mmHg increase, p = 3 × 10<jats:sup>−18</jats:sup>; DBP OR 1.27 [1.17–1.39], p = 4 × 10<jats:sup>−8</jats:sup>; PP OR 1.51 [1.38–1.64], p = 1 × 10<jats:sup>−20</jats:sup>) and CAD (SBP OR 1.37 [1.29–1.45], p = 2 × 10<jats:sup>−24</jats:sup>; DBP OR 1.6 [1.45–1.76], p = 7 × 10<jats:sup>−22</jats:sup>; PP OR 1.56 [1.4–1.75], p = 1 × 10<jats:sup>−15</jats:sup>). The effects of SBP and DBP were greater for CAD than PAD (p<jats:sub>diff</jats:sub>= 0.024 for SBP, p<jats:sub>diff</jats:sub>= 4.9 × 10<jats:sup>−4</jats:sup>for DBP). Increased liability to PAD increased PP (beta
Gill D, Walker VM, Martin RM, et al., 2020, Comparison with randomized controlled trials as a strategy for evaluating instruments in Mendelian randomization, International Journal of Epidemiology, Vol: 49, Pages: 1404-1406, ISSN: 0300-5771
Hyman MC, Levin MG, Gill D, et al., 2020, Blood Pressure and Risk of Atrial Fibrillation: A Mendelian Randomization Study
<jats:title>Abstract</jats:title><jats:sec><jats:title>Importance</jats:title><jats:p>Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>The primary objective of this study was to investigate the relationship between blood pressure and risk of AF using genetic proxies for blood pressure within a Mendelian randomization (MR) framework. We secondarily explored the relationship between genetically proxied use of anti-hypertensive drugs and risk of AF.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Two-sample MR was performed using an inverse-variance weighted meta-analysis with weighted median MR and Egger intercept tests performed as sensitivity analyses. Genetic proxies for the anti-hypertensive drug classes were used to investigate the impact of these therapies on the risk of AF.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>International Consortium of Blood Pressure, UK Biobank and Atrial Fibrillation Genetics Consortium.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Summary statistics for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis (>750,000 individuals of European ancestry).</jats:p><jats:p>Summary statistics for AF were obtained from the 2018 Atrial Fibrillation Genetics Consortium multi-ethnic GWAS (>65,000 AF cases and >522,000 referents).</jats:p></j
Georgakis MK, Gill D, Webb AJS, et al., 2020, Genetically determined blood pressure, antihypertensive drug classes and risk of stroke subtypes, Neurology, Vol: 95, Pages: e353-361, ISSN: 0028-3878
Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH.Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH.Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.
Gill D, Georgakis MK, Zuber V, et al., 2020, Genetically predicted midlife blood pressure and coronary artery disease risk: Mendelian randomization analysis, Journal of the American Heart Association, Vol: 9, ISSN: 2047-9980
BackgroundElevated blood pressure is a major cause of cardiovascular morbidity and mortality. However, it is not known whether midlife blood pressure affects later life cardiovascular risk independent of later life blood pressure.Methods and ResultsUsing genetic association estimates from the UK Biobank and CARDIoGRAMplusC4D consortium, univariable mendelian randomization was performed to investigate the total effect of genetically predicted mean arterial pressure (MAP) at age ≤55 years on coronary artery disease (CAD) risk, and multivariable mendelian randomization was performed to investigate the effect of genetically predicted MAP on CAD risk after adjusting for genetically predicted MAP at age >55 years. In both univariable and multivariable mendelian randomization analyses, there was consistent evidence of higher genetically predicted MAP at age ≤55 years increasing CAD risk. This association persisted after adjusting for genetically predicted MAP at age >55 years, when considering nonoverlapping populations for the derivation of MAP and CAD risk genetic association estimates, when investigating only incident CAD events after age >55 years, and when restricting the analysis to variants with most heterogeneity in their associations with MAP ≤55 and >55 years. For a 10–mm Hg increase in genetically predicted MAP at age ≤55 years, the odds ratio of later life CAD was 1.43 (95% CI, 1.16–1.77; P=0.001) after adjusting for genetically predicted MAP at age >55 years.ConclusionsThese mendelian randomization findings support a cumulative lifetime effect of elevated blood pressure on increasing CAD risk. Clinical and public health efforts toward cardiovascular disease reduction should optimize blood pressure control throughout life.
Ellingjord-Dale M, Papadimitriou N, Katsoulis M, et al., 2020, Coffee consumption and risk of breast cancer: a Mendelian Randomization study
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Observational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We conducted a two-sample Mendelian randomization randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>One cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR=0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The results of this large
Gill D, Zuber V, Dawson J, et al., 2020, Risk factors mediating the effect of body-mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Higher body-mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits and smoking is not fully understood.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, MR mediation analysis was performed to investigate the degree to which genetically predicted systolic blood pressure (SBP), diabetes, lipid traits and smoking mediated an effect of genetically predicted BMI and WHR on risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The 49% (95% confidence interval [CI] 39%-60%) increased risk of CAD conferred per 1-standard deviation increase in genetically predicted BMI attenuated to 34% (95% CI 24%-45%) after adjusting for genetically predicted SBP, to 27% (95% CI 17%-37%) after adjusting for genetically predicted diabetes, to 47% (95% CI 36%-59%) after adjusting for genetically predicted lipids, and to 46% (95% CI 34%-58%) after adjusting for genetically predicted smoking. Adjusting for all the mediators together, the increased risk attenuated to 14% (95% CI 4%-26%). A similar pattern of attenuation was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcomes.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Measures to reduce obesity will lower risk of cardiovascular disease primarily by impacting on downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongs
Walker VM, Harrison S, Carter AR, et al., 2020, The consequences of adjustment, correction and selection in genome-wide association studies used for two-sample Mendelian randomization
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Introduction</jats:title><jats:p>Genome-wide association studies (GWASs) often adjust for covariates, correct for medication use, or select on medication users. If these summary statistics are used in two-sample Mendelian randomization analyses, estimates may be biased. We used simulations to investigate how GWAS adjustment, correction and selection affects these estimates and performed an analysis in UK Biobank to provide an empirical example.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We simulated six GWASs: no adjustment for a covariate, correction for medication use, or selection on medication users; adjustment only; selection only; correction only; both adjustment and selection; and both adjustment and correction. We then ran two-sample Mendelian randomization analyses using these GWASs to evaluate bias. We also performed equivalent GWASs using empirical data from 306,560 participants in UK Biobank with systolic blood pressure as the exposure and body mass index as the covariate and ran two-sample Mendelian randomization with coronary heart disease as the outcome.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The simulation showed that estimates from GWASs with selection can produce biased two-sample Mendelian randomization estimates. Yet, we observed relatively little difference between empirical estimates of the effect of systolic blood pressure on coronary artery disease across the six scenarios.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Given the potential for bias from using GWASs with selection on Mendelian randomization estimates demonstrated in our simulation, careful consideration before using this approach is warranted. However, based on our empirical results, using adjusted, c
Georgakis MK, Gill D, Malik R, et al., 2020, Genetically predicted blood pressure across the lifespan: differential effects of mean and pulse pressure on stroke risk., Hypertension, Vol: 76, Pages: 953-961, ISSN: 0194-911X
Hypertension is the leading risk factor for stroke. Yet, it remains unknown whether blood pressure pulsatility (pulse pressure [PP]) causally affects stroke risk independently of the steady pressure component (mean arterial pressure [MAP]). It is further unknown how the effects of MAP and PP on stroke risk vary with age and stroke cause. Using data from UK Biobank (N=408 228; 38-71 years), we selected genetic variants as instruments for MAP and PP at age ≤55 and >55 years and across age deciles. We applied multivariable Mendelian randomization analyses to explore associations with ischemic stroke, intracerebral hemorrhage, and their subtypes. Higher genetically predicted MAP was associated with higher risk of ischemic stroke and intracerebral hemorrhage across the examined age spectrum. Independent of MAP, higher genetically predicted PP only at age >55 years was further associated with higher risk of ischemic stroke (odds ratio per-SD-increment, 1.23 [95% CI, 1.13-1.34]). Among subtypes, the effect of genetically predicted MAP on large artery stroke was attenuated, whereas the effect of genetically predicted PP was augmented with increasing age. Genetically predicted MAP, but not PP, was associated with small vessel stroke and deep intracerebral hemorrhage homogeneously across age deciles. Neither genetically predicted MAP nor PP were associated with lobar intracerebral hemorrhage. Beyond an effect of high MAP at any age on ischemic and hemorrhagic stroke, our results support an independent causal effect of high PP at older ages on large artery stroke. This finding warrants further investigation for the development of stroke preventive strategies targeting pulsatility in later life.
Zhang X, Gill D, He Y, et al., 2020, Non-genetic biomarkers and colorectal cancer risk: Umbrella review and evidence triangulation, Cancer Medicine, Vol: 9, Pages: 4823-4835, ISSN: 2045-7634
Several associations between non-genetic biomarkers and colorectal cancer (CRC) risk have been detected, but the strength of evidence and the direction of associations are not confirmed. We aimed to evaluate the evidence of these associations and integrate results from different approaches to assess causal inference. We searched Medline and Embase for meta-analyses of observational studies, meta-analyses of randomized clinical trials (RCTs), and Mendelian randomization (MR) studies measuring the associations between non-genetic biomarkers and CRC risk and meta-analyses of RCTs on supplementary micronutrients. We repeated the meta-analyses using random-effects models and categorized the evidence based on predefined criteria. We described each MR study and evaluated their credibility. Seventy-two meta-analyses of observational studies and 18 MR studies on non-genetic biomarkers and six meta-analyses of RCTs on micronutrient intake and CRC risk considering 65, 42, and five unique associations, respectively, were identified. No meta-analyses of RCTs on blood level biomarkers have been found. None of the associations were classified as convincing or highly suggestive, three were classified as suggestive, and 26 were classified as weak. For three biomarkers explored in MR studies, there was evidence of causality and seven were classified as likely noncausal. For the first time, results from both observational and MR studies were integrated by triangulating the evidence for a wide variety of non-genetic biomarkers and CRC risk. At blood level, lower vitamin D, higher homeostatic model assessment-insulin resistance, and human papillomavirus infection were associated with higher CRC risk while increased linoleic acid and oleic acid and decreased arachidonic acid were likely causally associated with lower CRC risk. No association was found convincing in both study types.
Falcone GJ, Kirsch E, Acosta JN, et al., 2020, Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage, ANNALS OF NEUROLOGY, Vol: 88, Pages: 56-66, ISSN: 0364-5134
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- Citations: 28
Carter AR, Gill D, Morris R, et al., 2020, Educational inequalities in statin treatment for preventing cardiovascular disease: cross-sectional analysis of UK Biobank
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The most socioeconomically deprived individuals remain at the greatest risk of cardiovascular disease. Differences in risk adjusted use of statins between educational groups may contribute to these inequalities. We explore whether people with lower levels of educational attainment are less likely to take statins for a given level of cardiovascular risk.</jats:p></jats:sec><jats:sec><jats:title>Methods and findings</jats:title><jats:p>Using data from a large prospective cohort study, UK Biobank, we calculated a QRISK3 cardiovascular risk score for 472 097 eligible participants with complete data on self-reported educational attainment and statin use (55% female; mean age, 56). We used logistic regression to explore the association between i) QRISK3 score and self-report statin use and ii) educational attainment and self-report statin use. We then stratified the association of QRISK3 score, and statin use by strata of educational attainment to test for an interaction. In this sample, greater education was associated with lower statin use, whilst higher cardiovascular risk (assessed by QRISK3 score) was associated with higher statin use in both females and males. There was evidence of an interaction between QRISK3 and education, such that for the same QRISK3 score, people with more education were more likely to report taking statins. For example, in women with 7 years of schooling, equivalent to leaving school with no formal qualifications, a one unit increase in QRISK3 score was associated with a 7% higher odds of statin use (odds ratio (OR) 1.07, 95% CI 1.07, 1.07). In contrast, in women with 20 years of schooling, equivalent to obtaining a degree, a one unit increase in QRISK3 score was associated with an 14% higher odds of statin use (OR 1.14, 95% CI 1.14, 1.15). Comparable ORs in men were 1.04 (95% CI 1.04, 1
Larsson SC, Gill D, Mason AM, et al., 2020, Lipoprotein(a) in Alzheimer, atherosclerotic, cerebrovascular, thrombotic, and valvular disease: mendelian randomization investigation., Circulation, Vol: 141, Pages: 1826-1828, ISSN: 0009-7322
Georgakis MK, Malik R, Gill D, et al., 2020, Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a mendelian randomization study., Circulation: Genomic and Precision Medicine, Vol: 13, Pages: 168-171, ISSN: 2574-8300
Wainberg M, Gill D, Su B, et al., 2020, Dopaminergic stimulants and risk of Parkinson’s disease
<jats:p>Parkinson’s disease is characterized by dopaminergic neurodegeneration in the substantia nigra. Although dopaminergic drugs are the mainstay of Parkinson’s treatment, their putative disease-modifying properties remain controversial. We explored whether prescription of dopaminergic stimulants for attention-deficit hyperactivity disorder (ADHD) might affect Parkinson’s incidence. We performed Cox survival analyses for outpatient Parkinson’s diagnosis among ADHD-diagnosed seniors in the Optum Clinformatics™ Data Mart de-identified administrative claims database, correcting for diverse demographic and socio-economic status covariates. We compared 5,683 sustained users (≥ 90 days) of dopaminergic stimulants to 252 sustained users of atomoxetine, a noradrenergic first-line ADHD medication. Parkinson’s incidence was reduced among sustained dopaminergic stimulant users compared to atomoxetine users (adjusted hazard ratio [HR] 0.15, 95% confidence interval [CI] 0.04-0.56, p = 0.005). Effect sizes were comparable between derivatives of amphetamine (adjusted HR 0.12, 95% CI 0.03-0.48, p = 0.003) and methylphenidate (adjusted HR 0.27, 95% CI 0.04-1.76, p = 0.2). In sensitivity analyses, similar trends were observed when other psychotropics (SSRIs, gabapentin) were used as comparators instead of atomoxetine, or when the threshold for sustained use was defined as 45, 180 or 360 days instead of 90. Thus, sustained dopaminergic stimulant use was associated with lower Parkinson’s incidence among seniors with ADHD. Our results are consistent with a protective effect of dopaminergic stimulants on the development of Parkinson’s, and support a re-examination of certain dopaminergics, particularly rasagiline and other selective monoamine oxidase B inhibitors, as potential disease-modifying agents.</jats:p>
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
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