Publications
312 results found
Carter A, Gill D, Morris R, et al., 2021, EDUCATIONAL INEQUALITIES IN STATIN TREATMENT: CROSS-SECTIONAL ANALYSIS OF UK BIOBANK, Publisher: BMJ PUBLISHING GROUP, Pages: A70-A70, ISSN: 0143-005X
Georgakis MK, Gill D, 2021, Mendelian Randomization Studies in Stroke Exploration of Risk Factors and Drug Targets With Human Genetic Data, STROKE, Vol: 52, Pages: 2992-3003, ISSN: 0039-2499
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- Citations: 14
Carter A, Gill D, Morris R, et al., 2021, Educational inequalities in primary prevention statin use in UK Biobank, Publisher: OXFORD UNIV PRESS, ISSN: 0300-5771
Coscia C, Gill D, Benítez R, et al., 2021, Avoiding bias in Mendelian randomization when stratifying on a collider
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Mendelian randomization (MR) uses genetic variants as instrumental variables to investigate the causal effect of a risk factor on an outcome. A collider is a variable influenced by two or more other variables. Naive calculation of MR estimates in strata of the population defined by a variable affected by the risk factor can result in collider bias.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We propose an approach that allows MR estimation in strata of the population while avoiding collider bias. This approach constructs a new variable, the residual collider, as the residual from regression of the collider on the genetic instrument, and then calculates causal estimates in strata defined by quantiles of the residual collider. Estimates stratified on the residual collider will typically have an equivalent interpretation to estimates stratified on the collider, but they are not subject to collider bias. We apply the approach in several simulation scenarios considering different characteristics of the collider variable and strengths of the instrument. We then apply the proposed approach to investigate the causal effect of smoking on bladder cancer in strata of the population defined by bodyweight.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The new approach generated unbiased estimates in all the simulation settings. In the applied example, we observed a trend in the stratum-specific MR estimates at different bodyweight levels that suggested stronger effects of smoking on bladder cancer among individuals with lower bodyweight.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The proposed approach can be used to perform MR studying heterogeneity among subgroups of the popu
Fatumo S, Kamiza A, Toure S, et al., 2021, Polygenic prediction of lipid traits in sub-Saharan Africans
<jats:title>Abstract</jats:title> <jats:p>Polygenic risk scores (PRS) can enhance risk stratification and are useful for precision medicine interventions. Here we show that African American Genome-wide Association Study (GWAS) derived PRS enhance prediction of lipid traits in Sub-Saharan Africans. Our PRS prediction varied greatly between South African Zulus (LDL-C, R2 = 8.49%) and Ugandans (LDL-C, R2= 0.043%), potentially attributable to environmental factors. Moreover, the PRS shown here had a higher discriminatory ability (AUC = 74.6%) than conventional risk factors (AUC= 67.8%) to identify extreme phenotypes. This work highlights the utility of PRS derived from relevant ethnic groups for identifying high-risk cases missed by conventional clinical factors.</jats:p>
Levin MG, Zuber V, Walker VM, et al., 2021, Prioritizing the role of major lipoproteins and subfractions as risk factors for peripheral artery disease, Circulation, Vol: 144, Pages: 353-364, ISSN: 0009-7322
Background:Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk.Methods:Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies.Results:ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; P=0.003) and CAD (marginal inclusion probability, 0.92; P=0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84–0.91]; P=9×10−10) and CAD (odds ratio,0.66 [95% CI, 0.63–0.69]; P=4×10−73), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29–4.60]; P<1×10−6). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; P=2.3×10−4), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; P=0.011). Genes associated with extr
Fatumo S, Karhunen V, Chikowore T, et al., 2021, Metabolic traits and stroke risk in individuals of African ancestry: Mendelian randomization analysis, Stroke, Vol: 52, Pages: 2680-2684, ISSN: 0039-2499
Background and Purpose:Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals.Methods:For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy.Results:Higher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07–1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04–1.21]; total cholesterol: 1.23 [1.06–1.43]; HDL-C, 0.93 [0.89–0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals.Conclusions:Our analyses support
Rogne T, Liyanarachi K, Rasheed H, et al., 2021, GWAS Identifies <i>LINC01184/SLC12A2</i> as a Risk Locus for Skin and Soft Tissue Infections, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 141, Pages: 2083-+, ISSN: 0022-202X
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- Citations: 1
Larsson SC, Gill D, 2021, Association of serum magnesium levels with risk of intracranial aneurysm a mendelian randomization study, Neurology, Vol: 97, Pages: E341-E344, ISSN: 0028-3878
Objective Magnesium has been implicated in regulating blood pressure and vascular endothelial cell function, but its role in the pathophysiology of intracranial aneurysm is not known. Here we performed a Mendelian randomization analysis to investigate the association between serum magnesium concentration and risk of intracranial aneurysm.Methods Five single-nucleotide polymorphisms strongly associated with serum magnesium concentrations in a genome-wide association study in 23,829 individuals of European ancestry were used as genetic instruments. Genetic association estimates for intracranial aneurysm were obtained from a genome-wide association study in 79,429 individuals (7,495 cases and 71,934 controls). The inverse variance weighted method was used in the primary analyses to obtain the causal estimates.Results Higher genetically predicted serum magnesium concentrations were associated with lower risk of intracranial aneurysm. The odds ratios per 0.1 mmol/L increment in genetically predicted serum magnesium concentrations were 0.66 (95% confidence interval [CI] 0.49–0.91) for intracranial aneurysm (unruptured and ruptured combined), 0.57 (95% CI 0.30–1.06) for unruptured intracranial aneurysm, and 0.67 (95% CI 0.48–0.92) for aneurysmal subarachnoid hemorrhage.Conclusion This study provides evidence to support that increased serum magnesium concentrations reduce the risk of intracranial aneurysm and associated hemorrhage.
Giontella A, Lotta LA, Overton JD, et al., 2021, Causal effect of adiposity measures on blood pressure traits in 2 urban Swedish cohorts: a mendelian randomization study, Journal of the American Heart Association, Vol: 10, Pages: 1-23, ISSN: 2047-9980
BackgroundDifferent adiposity traits may be causally related to hypertension in different ways. By using genetic variants as randomly allocated proxies for studying the effect of modifying adiposity traits, the Mendelian randomization approach can be used to investigate this.Methods and ResultsIn this study, we used 4 different genetic risk scores (GRS; GRS‐BMI565, GRS‐WHR324, GRS‐VAT208, GRS‐BF81) including hundreds of single nucleotide polymorphisms associated with body mass index, waist‐to‐hip ratio, visceral adipose tissue, and body fat, respectively. These were applied as instrumental variables in Mendelian randomization analyses. Two Swedish urban‐based cohort studies, the Malmö Diet and Cancer, and the Malmö Preventive 795Projects were used to obtain genetic association estimates with blood pressure (BP). In both the Malmö Preventive Projects and Malmö Diet and Cancer studies, except for that for body fat, all of the genetic risk scores were significantly associated with systolic BP and diastolic BP, but with different magnitudes. In particular, in both cohorts, each standard deviation increase in the genetic risk score made up by the 324 single nucleotide polymorphisms associated with waist‐to‐hip ratio was associated with doubling of the likelihood of hypertension prevalence at baseline. However, only the genetic risk score made up by the 565 SNPs associated with body mass index was significantly associated with hypertension incidence during 23.6±4.3 years of follow‐up in the Malmö Preventive Project.ConclusionsWe support a causal link between genetically mediated adiposity, especially waist‐to‐hip ratio and body mass index, and BP traits including hypertension prevalence and, for the first time to our knowledge, hypertension incidence. The differences in magnitude between these associations might suggest different mechanisms by which different adiposity affects BP/hypertension and consequently may indicate that tailored inte
Gill D, Zuber V, Dawson J, et al., 2021, Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis, International Journal of Obesity, Vol: 45, Pages: 1428-1438, ISSN: 0307-0565
BackgroundHigher 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.MethodsUsing consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke.ResultsThe odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% −23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI −20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome.ConclusionsMeasures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.
Auvinen J, Tapio J, Karhunen V, et al., 2021, Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia, Science Advances, Vol: 7, Pages: 1-12, ISSN: 2375-2548
Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (n = 7175) and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes SLC2A4 and Slc2a1 in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.
Carcel-Marquez J, Cullell N, Muino E, et al., 2021, Causal Effect of MMP-1 (Matrix Metalloproteinase-1), MMP-8, and MMP-12 Levels on Ischemic Stroke A Mendelian Randomization Study, STROKE, Vol: 52, Pages: E316-E320, ISSN: 0039-2499
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- Citations: 12
Gill D, 2021, Genetic evidence for repurposing of glucagon-like peptide-1 receptor agonists to prevent heart failure, Journal of the American Heart Association, Vol: 10, ISSN: 2047-9980
Background: To investigate the genetic evidence for repurposing of glucagon-like peptide-1 receptor (GLP1R) agonists to prevent heart failure (HF) and whether the potential benefit exceeds the benefit conferred by more general glycemic control. Methods and Results: We applied two-sample Mendelian randomization of genetically proxied GLP1R agonism on HF as the main outcome and left ventricular ejection fraction (LVEF) as the secondary outcome. The associations were compared to those of general glycemic control on the same outcomes. Genetic associations were obtained from genome-wide association study summary statistics of type 2 diabetes (228,499 cases and 1,178,783 controls), glycated hemoglobin (n=344,182), HF (47,309 cases and 930,014 controls), and LVEF (n=16,923). Genetic proxies for GLP1R agonism associated with reduced risk of HF (odds ratio per 1mmol/mol decrease in glycated hemoglobin 0.75, 95% confidence interval 0.64-0.87, P=1.69x10-4), and higher LVEF (standard deviation change in LVEF per 1mmol/mol decrease in glycated hemoglobin 0.22, 95% confidence interval 0.03-0.42, P=0.03). The magnitude of these benefits exceeded those expected from improved glycemic control more generally. The results were similar in sensitivity analyses, and we did not find evidence to suggest that these associations were mediated by reduced coronary artery disease risk. Conclusions: This genetic evidence supports the re-purposing of GLP1R agonists for preventing HF.
Bonanni P, Cantón R, Gill D, et al., 2021, The Role of Serology Testing to Strengthen Vaccination Initiatives and Policies for COVID-19 in Europe, COVID, Vol: 1, Pages: 20-38
<jats:p>This review explores and positions the value of serology testing to support current immunization policies and the broader policy response to the coronavirus disease 2019 (COVID-19) crisis in Europe. We applied an exploratory approach to analysing existing evidence, international recommendations, and national policies using desk research from secondary sources, document analysis, and expert information. Regional and country-level resources from five focus countries were included: France, Germany, Italy, Spain, and the United Kingdom. Seven experts in the fields of COVID-19 immunization, serology testing, seroepidemiology, and vaccine safety and effectiveness studies contributed to the review and convened in two online panel sessions. The paper includes an overview of (1) the impact of the pandemic to date, (2) testing strategies, (3) COVID-19 vaccination policies, (4) lessons on using serology testing to support immunization, (5) current policies and recommendations on the use of a serology testing strategy, and (6) implementation barriers and challenges. Finally, this paper also provides a set of knowledge-based recommendations to advance the effective and timely inclusion of serology testing and resolve impeding knowledge gaps. The recommendations herein are intended to support timely decision-making, raise awareness, guide advocacy initiatives, and inspire future studies.</jats:p>
Rahman R, McEwan L, Ryan D, et al., 2021, Leveraging genetic data to investigate the effects of interleukin-6 receptor signalling on levels of 40 circulating cytokines.
<jats:p id="p1">Abstract Interleukin 6 (IL-6) is a circulating cytokine that isimplicated in a range of inflammatory diseases. However, the broadeffects of IL-6 receptor (IL-6R) signalling on other circulatingcytokines is not known. Using summary-level data from genome-wideassociation studies, we leveraged genetic variants that proxy IL-6Rsignalling in two-sample Mendelian randomization analyses to investigateeffects on levels of 40 circulating cytokines. Increased geneticallyproxied IL-6R signalling was associated with reduced levels of 10circulating interleukins, chemokines, and growth factors. The findingsfrom this study support feedback effects of IL-6R signalling on reducinglevels of a range of circulating cytokines and identify compensatorymechanisms that may be modulating its inflammatory effects. Theseresults provide novel insight into the mechanisms by which IL-6Rsignalling may be contributing to inflammatory and autoimmune diseases.</jats:p>
Larsson SC, Gill D, 2021, Genetic predisposition to allergic diseases is inversely associated with risk of COVID-19, Allergy, Vol: 76, Pages: 1911-1913, ISSN: 0105-4538
Malik R, Georgakis MK, Vujkovic M, et al., 2021, Relationship between blood pressure and incident cardiovascular disease. Linear and non-linear Mendelian randomization analyses, Hypertension, Vol: 77, Pages: 2004-2013, ISSN: 0194-911X
Observational studies exploring whether there is a nonlinear effect of blood pressure on cardiovascular disease (CVD) risk are hindered by confounding. This limitation can be overcome by leveraging randomly allocated genetic variants in nonlinear Mendelian randomization analyses. Based on their association with blood pressure traits in a genome-wide association study of 299 024 European ancestry individuals, we selected 253 genetic variants to proxy the effect of modifying systolic and diastolic blood pressure. Considering the outcomes of incident coronary artery disease, stroke and the combined outcome of CVD, linear and nonlinear Mendelian randomization analyses were performed on 255 714 European ancestry participants without a history of CVD or antihypertensive medication use. There was no evidence favoring nonlinear relationships of genetically proxied systolic and diastolic blood pressure with the cardiovascular outcomes over linear relationships. For every 10-mm Hg increase in genetically proxied systolic blood pressure, risk of incident CVD increased by 49% (hazard ratio, 1.49 [95% CI, 1.38–1.61]), with similar estimates obtained for coronary artery disease (hazard ratio, 1.50 [95% CI, 1.38–1.63]) and stroke (hazard ratio, 1.44 [95% CI, 1.22–1.70]). Genetically proxied blood pressure had a similar relationship with CVD in men and women. These findings provide evidence to support that even for individuals who do not have elevated blood pressure, public health interventions achieving persistent blood pressure reduction will be of considerable benefit in the primary prevention of CVD.
Tsilidis KK, Papadimitriou N, Dimou N, et al., 2021, Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study, American Journal of Clinical Nutrition, Vol: 113, Pages: 1490-1502, ISSN: 0002-9165
BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVES: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULTS: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetica
Pearson-Stuttard J, Papadimitriou N, Markozannes G, et al., 2021, Type 2 diabetes and cancer: an umbrella review of observational and Mendelian randomisation studies, Cancer Epidemiology, Biomarkers and Prevention, Vol: 30, Pages: 1218-1228, ISSN: 1055-9965
Background Type 2 diabetes(T2DM) has been associated with an increased risk of developing several common cancers, but it is unclear whether this association is causal. We aimed to summarise the evidence on T2DM and cancer and evaluate the validity of associations from both observational and Mendelian randomisation(MR) studies. Methods We performed an umbrella review of the evidence across meta-analyses of observational studies that examined associations of T2DM with risk of developing or dying from site-specific cancers, and MR studies that explored the potential causal association of T2DM and associated biomarkers with cancer risk. Results We identified eligible observational meta-analyses that assessed associations between T2DM and cancer incidence for 18 cancer sites, cancer mortality for seven sites, and cancer incidence or mortality for four sites. Positive associations between T2DM and six cancers reached strong or highly suggestive evidence. We found eight MR studies assessing the association of genetically predicted T2DM and seven and eight studies assessing the association of genetically predicted fasting insulin or fasting glucose concentrations, respectively, upon site-specific cancers. Positive associations were found between genetically predicted T2DM and fasting insulin and risk of six cancers. There was no association between genetically predicted fasting plasma glucose and cancer except for squamous cell lung carcinoma. Conclusions We found robust observational evidence for the association between T2DM and colorectal, hepatocellular, gallbladder, breast, endometrial and pancreatic cancer. Impact Potential causal associations were identified for genetically predicted T2DM and fasting insulin concentrations and risk of endometrial, pancreas, kidney, breast, lung and cervical cancer.
Zuber V, Gill D, Ala-Korpela M, et al., 2021, High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease, International Journal of Epidemiology, Vol: 50, Pages: 893-901, ISSN: 0300-5771
BackgroundGenetic 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.MethodsAs 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 supplementary and sensitivity analyses varying the dataset for genetic associations with CAD.ResultsIn 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 sensitivity analyses. No other measure of cholesterol or triglyceride is consistently selected otherwise.ConclusionsOur agnostic genetic investigation prioritizes ApoB across all datasets considered, suggesting that ApoB, representing the total number of hepatic-derived lipoprotein particles, is the primary lipid determinant of CAD.
Levin MG, Klarin D, Walker VM, et al., 2021, Association Between Genetic Variation in Blood Pressure and Increased Lifetime Risk of Peripheral Artery Disease, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 41, Pages: 2027-2034, ISSN: 1079-5642
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- Citations: 11
Malik R, Georgakis MK, Vujkovic M, et al., 2021, Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses, Hypertension, Vol: 77, Pages: 2004-2013, ISSN: 0194-911X
<jats:p>Observational studies exploring whether there is a nonlinear effect of blood pressure on cardiovascular disease (CVD) risk are hindered by confounding. This limitation can be overcome by leveraging randomly allocated genetic variants in nonlinear Mendelian randomization analyses. Based on their association with blood pressure traits in a genome-wide association study of 299 024 European ancestry individuals, we selected 253 genetic variants to proxy the effect of modifying systolic and diastolic blood pressure. Considering the outcomes of incident coronary artery disease, stroke and the combined outcome of CVD, linear and nonlinear Mendelian randomization analyses were performed on 255 714 European ancestry participants without a history of CVD or antihypertensive medication use. There was no evidence favoring nonlinear relationships of genetically proxied systolic and diastolic blood pressure with the cardiovascular outcomes over linear relationships. For every 10-mm Hg increase in genetically proxied systolic blood pressure, risk of incident CVD increased by 49% (hazard ratio, 1.49 [95% CI, 1.38–1.61]), with similar estimates obtained for coronary artery disease (hazard ratio, 1.50 [95% CI, 1.38–1.63]) and stroke (hazard ratio, 1.44 [95% CI, 1.22–1.70]). Genetically proxied blood pressure had a similar relationship with CVD in men and women. These findings provide evidence to support that even for individuals who do not have elevated blood pressure, public health interventions achieving persistent blood pressure reduction will be of considerable benefit in the primary prevention of CVD.</jats:p>
Smith D, Gill D, 2021, Antivirals against SARS-CoV-2 by autumn?, BMJ-BRITISH MEDICAL JOURNAL, Vol: 373, ISSN: 0959-535X
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- Citations: 2
Pazoki R, Elliott J, Evangelou E, et al., 2021, Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes, Nature Communications, Vol: 12, ISSN: 2041-1723
Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
Walker V, Harrison S, Carter A, et al., 2021, The consequences of adjustment, correction and selection in genome-wide association studies used for two-sample Mendelian randomization, Wellcome Open Research, Vol: 6, Pages: 103-103
<ns4:p><ns4:bold>Introduction</ns4:bold>: 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.</ns4:p><ns4:p> <ns4:bold>Methods</ns4:bold>: 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.</ns4:p><ns4:p> <ns4:bold>Results</ns4:bold>: 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.</ns4:p><ns4:p> <ns4:bold>Conclusions</ns4:bold>: 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, corrected or selected GWASs is unlikely to make a large difference to two-sample Mendelian randomization estimates in practice.</ns4:p>
Larsson SC, Gill D, 2021, Genetic evidence supporting fibroblast growth factor 21 signalling as a pharmacological target for cardiometabolic outcomes and Alzheimer's disease, Nutrients, Vol: 13, Pages: 1-5, ISSN: 2072-6643
Fibroblast growth factor 21 (FGF21) is a human metabolic hormone whose effects include modification of macronutrient preference and energy homeostasis. In animal models, FGF21 has been shown to have beneficial effects on cardiometabolic outcomes, Alzheimer’s disease risk and lifespan. In this study, the single-nucleotide polymorphism rs838133 in the FGF21 gene region was leveraged to investigate the potential clinical effects of targeting FGF21. The FGF21 G allele was associated with lower intakes of total sugars and alcohol, and higher intakes of protein and fat as well as favourable with lipid levels, blood pressure traits, waist-to-hip ratio, systemic inflammation, cardiovascular outcomes, Alzheimer’s disease risk and lifespan. These findings may be used to anticipate the effects of pharmacologically increasing FGF21 signalling.
Gill D, Baker EH, Hitchings AW, 2021, We need clinical guidelines fit for a pandemic, BMJ-BRITISH MEDICAL JOURNAL, Vol: 373, ISSN: 0959-535X
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- Citations: 6
Yuan S, Burgess S, Laffan M, et al., 2021, Genetically proxied inhibition of coagulation factors and risk of cardiovascular disease: a mendelian randomization study, Journal of the American Heart Association, Vol: 10, Pages: 1-20, ISSN: 2047-9980
BackgroundWe conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases.Methods and ResultsGenetic instruments proxying coagulation factor inhibition were identified from genome‐wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age‐ and sex‐adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome‐wide Replication and Meta‐analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (P<0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke (P≤0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large‐artery stroke risk (P=0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke (P<0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage.ConclusionsThis study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.
Grant AJ, Gill D, Kirk PDW, et al., 2021, Noise-augmented directional clustering of genetic association data identifies distinct mechanisms underlying obesity
<jats:title>Abstract</jats:title><jats:p>Clustering genetic variants based on their associations with different traits can provide insight into their underlying biological mechanisms. Existing clustering approaches typically group variants based on the similarity of their association estimates for various traits. We present a new procedure for clustering variants based on their proportional associations with different traits, which is more reflective of the underlying mechanisms to which they relate. The method is based on a mixture model approach for directional clustering and includes a noise cluster that provides robustness to outliers. The procedure performs well across a range of simulation scenarios. In an applied setting, clustering genetic variants associated with body mass index generates groups reflective of distinct biological pathways. Mendelian randomization analyses support that the clusters vary in their effect on coronary heart disease, including one cluster that represents elevated body mass index with a favourable metabolic profile and reduced coronary heart disease risk. Analysis of the biological pathways underlying this cluster identifies inflammation as playing a key role in mediating the effects of increased body mass index on coronary heart disease.</jats:p>
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