Publications
309 results found
Carter AR, Harrison S, Gill D, et al., 2021, Educational attainment as a modifier of the effect of polygenic scores for cardiovascular risk factors: cross-sectional and prospective analysis of UK Biobank
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Understanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of mechanisms relating educational attainment to cardiovascular disease.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In up to 320 120 UK Biobank participants of White British ancestry (mean age = 57, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>On the additive scale, higher educational attainment reduced genetic susceptibility to higher BMI, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure.</jats:p><jats:p>On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but no evidence of effect modification was found for all other considered traits.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Educational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by edu
Georgakis MK, Malik R, Li X, et al., 2021, Genetically Downregulated Interleukin-6 Signaling Is Associated With a Favorable Cardiometabolic Profile A Phenome-Wide Association Study, CIRCULATION, Vol: 143, Pages: 1177-1180, ISSN: 0009-7322
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Gill D, Karhunen V, Malik R, et al., 2021, Cardiometabolic traits mediating the effect of education on osteoarthritis risk: a Mendelian randomization study, Osteoarthritis and Cartilage, Vol: 29, Pages: 365-371, ISSN: 1063-4584
ObjectiveTo investigate which cardiometabolic factors underlie clustering of osteoarthritis (OA) with cardiovascular disease, and the extent to which these mediate an effect of education.DesignGenome-wide association study (GWAS) of OA was performed in UK Biobank (60,800 cases and 328,251 controls) to obtain genetic association estimates for OA risk. Genetic instruments and association estimates for body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP), smoking and education were obtained from existing GWAS summary data (sample sizes 188,577–866,834 individuals). Two-sample Mendelian randomization (MR) analyses were performed to investigate the effects of exposure traits on OA risk. MR mediation analyses were undertaken to investigate whether the cardiometabolic traits mediate any effect of education on OA risk.ResultsMR analyses identified protective effects of higher genetically predicted education (main MR analysis odds ratio (OR) per standard deviation increase 0.59, 95% confidence interval (CI) 0.54–0.64) and LDL-C levels (OR 0.94, 95%CI 0.91–0.98) on OA risk, and unfavourable effects of higher genetically predicted BMI (OR 1.82, 95%CI 1.73–1.92) and smoking (OR 2.23, 95%CI 1.85–2.68). There was no strong evidence of an effect of genetically predicted SBP on OA risk (OR 0.98, 95% CI 0.90–1.06). The proportion of the effect of genetically predicted education mediated through genetically predicted BMI and smoking was 35% (95%CI 13–57%).ConclusionsThese findings highlight education, obesity and smoking as common mechanisms underlying OA and cardiovascular disease. These risk factors represent clinical and public health targets for reducing multi-morbidity related to the burden these common conditions.
Larsson S, Gill D, 2021, Genetic evidence supporting fibroblast growth factor 21 signalling as a pharmacological target for cardiometabolic outcomes and Alzheimer's disease
<jats:p id="p1">Fibroblast growth factor 21 (FGF21) is a human metabolic hormone that isbeing pursued in early stage clinical trials as pharmacological targetto treat a range of metabolic diseases. In animal models, increasedFGF21 signalling has been shown to have beneficial effects oncardiometabolic outcomes, Alzheimer’s disease risk and lifespan.However, studies investigating the effect of FGF21 signalling on theseclinical outcomes in humans have been inconclusive. In this study, agenetic variant associated with higher circulating FGF21 levels wasleveraged to investigate its clinical effects in humans. Highergenetically proxied circulating FGF21 levels were associated favourablywith lipid levels, blood pressure traits, waist-to-hip ratio, chronicinflammation, cardiovascular outcomes, Alzheimer’s disease risk andlifespan. These findings may be used to anticipate the effects ofpharmacologically increasing FGF21 signalling and inform the design offurther clinical trials.</jats:p>
Chikowore T, Ekoru K, Vujkovic M, et al., 2021, Polygenic prediction of type 2 diabetes in continental Africa
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Polygenic prediction of type 2 diabetes in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa, and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans.</jats:p></jats:sec><jats:sec><jats:title>Research Design and Methods</jats:title><jats:p>Using the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS of the Million Veteran Program (MVP) study. The South African Zulu study (1602 cases and 976 controls) was used as the target data set. Replication and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (1031 cases and 738 controls).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The African American derived PRS was more predictive of type 2 diabetes compared to the European and multi-ethnic derived scores. Notably, participants in the 10<jats:sup>th</jats:sup> decile of this PRS had a 3.19-fold greater risk (OR 3.19; 95%CI (1.94-5.29), p = 5.33 x10<jats:sup>-6</jats:sup>) of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>African American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-Europeans populations (including Africans) in GWAS, promises to provide better tools for precision medicine interventions in type 2 diabetes.</j
Ryan DK, Karhunen V, Walker DJ, et al., 2021, Inhibition of interleukin 6 signalling and renal function: A Mendelian randomization study, British Journal of Clinical Pharmacology, Vol: 2021, Pages: 1-14, ISSN: 0306-5251
Inhibition of interleukin 6 (IL‐6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD), but the direct effects of IL‐6 inhibition on renal function are not known. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL‐6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse‐variance weighted MR was used as the main analysis, with sensitivity analyses performed using simple median, weighted median and MR‐Egger methods. There was no evidence for an association of genetically proxied inhibition of IL‐6 signalling (scaled per standard deviation unit decrease in C‐reactive protein) with log eGFR (0.001, 95% confidence interval −0.004‐0.007), BUN (0.009, 95% confidence interval −0.003‐0.021) and CKD (odds ratio 0.948, 95% confidence interval 0.822‐1.094). These findings do not raise concerns for IL‐6 signalling having large adverse effects on renal function.
Gill D, Georgakis MK, Walker VM, et al., 2021, Mendelian randomization for studying the effects of perturbing drug targets., Wellcome Open Res, Vol: 6, Pages: 1-19, ISSN: 2398-502X
Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline.
Higgins H, Mason AM, Larsson SC, et al., 2021, Estimating the Population Benefits of Blood Pressure Lowering: A Wide-Angled Mendelian Randomization Study in UK Biobank
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The causal relevance of elevated blood pressure for several cardiovascular diseases is uncertain, as is the population impact of blood pressure lowering on risk of cardiovascular diseases more broadly. This study systematically assesses evidence of causality for various cardiovascular diseases in a two-sample Mendelian randomization framework, and estimates the potential reduction in the prevalence of these diseases attributable to long-term population shifts in the distribution of systolic blood pressure (SBP).</jats:p></jats:sec><jats:sec><jats:title>Methods and Results</jats:title><jats:p>We investigated associations of genetically-predicted SBP as predicted by 256 genetic variants with 21 cardiovascular diseases in UK Biobank, a population-based cohort of UK residents. The sample consisted of 376,703 participants of European ancestry aged 40-69 years at baseline. Genetically-predicted SBP was positively associated with 14 of the outcomes (p<0.002), including dilated cardiomyopathy, endocarditis, peripheral vascular disease, and rheumatic heart disease. Using genetic variation to estimate the long-term impact of blood pressure lowering on disease, population reductions in SBP were predicted to result in an overall 16.9% (95% confidence interval (CI): 12.2-21.3%) decrease in morbidity for a 5 mmHg decrease from a population mean of 137.7 mmHg, 30.8% (95% CI: 22.8-38.0%) for a 10 mmHg decrease, and 56.2% (95% CI: 43.7-65.9%) decrease for a 22.7 mmHg decrease in SBP (22.7 mmHg represents a shift from the current mean SBP to 115 mmHg).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Risk of many cardiovascular diseases is influenced by long-term differences in SBP. The burden of a broad range of CVDs could be substantially reduced by long-term p
Gill D, Cameron AC, Burgess S, et al., 2021, Urate, blood pressure and cardiovascular disease: evidence from Mendelian randomization and meta-analysis of clinical trials, Hypertension, Vol: 77, Pages: 383-392, ISSN: 0194-911X
Serum urate has been implicated in hypertension and cardiovascular disease, but it is not known whether it is exerting a causal effect. To investigate this, we performed Mendelian randomization analysis using data from UK Biobank, Million Veterans Program and genome-wide association study consortia, and meta-analysis of randomized controlled trials. The main Mendelian randomization analyses showed that every 1-SD increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio, 1.19 [95% CI, 1.10–1.30]; P=4×10−5), peripheral artery disease (1.12 [95% CI, 1.03–1.21]; P=9×10−3), and stroke (1.11 [95% CI, 1.05–1.18]; P=2×10−4). In Mendelian randomization mediation analyses, elevated blood pressure was estimated to mediate approximately one-third of the effect of urate on cardiovascular disease risk. Systematic review and meta-analysis of randomized controlled trials showed a favorable effect of urate-lowering treatment on systolic blood pressure (mean difference, −2.55 mm Hg [95% CI, −4.06 to −1.05]; P=1×10−3) and major adverse cardiovascular events in those with previous cardiovascular disease (odds ratio, 0.40 [95% CI, 0.22–0.73]; P=3×10−3) but no significant effect on major adverse cardiovascular events in all individuals (odds ratio, 0.67 [95% CI, 0.44–1.03]; P=0.07). In summary, these Mendelian randomization and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on cardiovascular disease risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate lowering may be of cardiovascular benefit.
Papadimitriou N, Dimou N, Gill D, et al., 2021, Genetically predicted circulating concentrations of micro-nutrients and risk of breast cancer: A Mendelian randomization study, International Journal of Cancer, Vol: 148, Pages: 646-653, ISSN: 0020-7136
The epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micro-nutrients and breast cancer risk. We investigated associations between genetically predicted concentrations of 11 micro-nutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6, vitamin B12 and zinc) and breast cancer risk using Mendelian randomization (MR). A two-sample MR study was conducted using 122,977 women with breast cancer and 105,974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions. One standard deviation (SD: 0.08 mmol/L) higher genetically predicted concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10 to 1.25, P-value=9.1 ×10-7 ) and 20% (OR: 1.20, 95% CI: 1.08 to 1.34, P-value=3.2×10-6 ) higher risk of overall and ER+ve breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically predicted phosphorus concentration and ER-ve breast cancer (OR: 0.84, 95% CI: 0.72 to 0.98, P-value=0.03). There was little evidence that any other nutrient was associated with breast cancer. The results for magnesium were robust under all sensitivity analyses and survived correction for multiple comparisons. Higher circulating concentrations of magnesium and potentially phosphorus may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.
Hyman MC, Levin MG, Gill D, et al., 2021, Genetically predicted blood pressure and risk of atrial fibrillation., Hypertension, Vol: 77, Pages: 376-382, ISSN: 0194-911X
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. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 [95% CI, 1.11-1.22]; P=1×10-11; diastolic blood pressure: OR, 1.25 [95% CI, 1.16-1.35]; P=3×10-8; pulse pressure: OR, 1.1 [95% CI, 1.0-1.2]; P=0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers (OR, 0.66 [95% CI, 0.57-0.76]; P=8×10-9) and β-blockers (OR, 0.61 [95% CI, 0.46-0.81]; P=6×10-4) decreased the risk of AF. Blood pressure-increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or β-blockade could reduce the risk of AF.
Reynolds CJ, Yates TA, Gill D, et al., 2021, MENDELIAN RANDOMIZATION STUDY OF CIGARETTE SMOKING IN IDIOPATHIC PULMONARY FIBROSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A47-A48, ISSN: 0040-6376
Burgess S, Malik R, Liu B, et al., 2021, Dose-response relationship between genetically proxied average blood glucose levels and incident coronary heart disease in individuals without diabetes mellitus, Diabetologia, Vol: 64, Pages: 845-849, ISSN: 0012-186X
Aims/hypothesisOur aim was to investigate the relationship between average blood glucose levels and incident CHD in individuals without diabetes mellitus.MethodsTo investigate average blood glucose levels, we studied HbA1c as predicted by 40 variants previously shown to be associated with both type 2 diabetes and HbA1c. Linear and non-linear Mendelian randomisation analyses were performed to investigate associations with incident CHD risk in 324,830 European ancestry individuals from the UK Biobank without diabetes mellitus.ResultsEvery one mmol/mol increase in genetically proxied HbA1c was associated with an 11% higher CHD risk (HR 1.11, 95% CI 1.05, 1.18). The dose–response curve increased at all levels of HbA1c, and there was no evidence favouring a non-linear relationship over a linear one.Conclusions/interpretationsIn individuals without diabetes mellitus, lowering average blood glucose levels may reduce CHD risk in a dose-dependent way.
Ellingjord-Dale M, Papadimitriou N, Katsoulis M, et al., 2021, Coffee consumption and risk of breast cancer: A Mendelian randomization study, PLoS One, Vol: 16, ISSN: 1932-6203
Background:Observational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer.Methods:We conducted a two-sample Mendelian 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.Results: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).Conclusions:The results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak association.
Karhunen V, Larsson S, Gill D, 2021, Genetically proxied growth differentiation factor 15 levels and body mass index
<jats:p id="p1">Growth-differentiation factor 15 (GDF15) is an inflammatory cytokineinvolved in energy homeostasis. Its circulating levels are acutelyincreased by the type 2 diabetes medication metformin, resulting inreduced appetite and weight loss. We identified a genetic variant at theGDF15 gene to proxy a small, lifelong increase in circulating GDF15levels, and leveraged it in colocalization and Mendelian randomizationanalyses to investigate the effects of chronically elevated GDF15 levelson body mass index (BMI) and type 2 diabetes liability. The resultsprovide human genetic evidence supporting that chronically elevatedGDF15 levels increase BMI. There was no genetic evidence to supportbi-directional effects, or that chronically elevated GDF15 levelsdirectly affect liability to type 2 diabetes. Our results contrast theBMI lowering effects of an acute increase in GDF15 levels observed aftermetformin use. These findings have direct implications for informingpharmacological strategies aimed at targeting GDF15 levels for weightloss.</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
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Circulating lipid and lipoprotein levels have consistently been identified as risk factors for atherosclerotic cardiovascular disease (ASCVD), largely on the basis of studies focused on coronary artery disease (CAD). The relative contributions of specific lipoproteins to risk of peripheral artery disease (PAD) have not been well-defined. Here, we leveraged large scale genetic association data to identify genetic proxies for circulating lipoprotein-related traits, and employed Mendelian randomization analyses to investigate their effects on PAD risk.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Genome-wide association study summary statistics for PAD (Veterans Affairs Million Veteran Program, 31,307 cases) and CAD (CARDIoGRAMplusC4D, 60,801 cases) were used in the Mendelian Randomization Bayesian model averaging (MR-BMA) 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 lowering on PAD risk using gene regions that proxy potential lipid-lowering drug targets. Transcriptome-wide association studies were performed to identify genes relevant to circulating levels of prioritized lipoprotein subfractions.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 (OR 0.87 per 1 standard deviation decrease in ApoB, 95% CI 0.84 to 0.91, p = 9 × 10<jats:sup>−10</jats:sup>) and CAD (OR 0.66, 95% CI 0.63 to 0.69
Larsson SC, Burgess S, Gill D, 2021, Genetically proxied interleukin-6 receptor inhibition: opposing associations with COVID-19 and pneumonia, European Respiratory Journal, Vol: 57, Pages: 1-3, ISSN: 0903-1936
Respiratory disease is a main feature of severe COVID-19, and the potential of IL-6 receptor blockade to increase risk of pneumonia warrants vigilance and caution in their application to treat COVID-19.
Vujkovic M, Ramdas S, Lorenz KM, et al., 2021, A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation
<jats:title>Abstract</jats:title><jats:p>Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic alanine aminotransferase elevation (cALT) without other liver diseases, we performed a trans-ancestry genome-wide association study in the Million Veteran Program including 90,408 cALT cases and 128,187 controls. In the Discovery stage, seventy-seven loci exceeded genome-wide significance – including 25 without prior NAFLD or ALT associations – with one additional locus identified in European-American-only and two in African-American-only analyses (P<5×10<jats:sup>-8</jats:sup>). External replication in cohorts with NAFLD defined by histology (7,397 cases, 56,785 controls) or liver fat extracted from radiologic imaging (n=44,289) validated 17 SNPs (P<6.5×10<jats:sup>-4</jats:sup>) of which 9 were novel (<jats:italic>TRIB1</jats:italic>,<jats:italic>PPARG</jats:italic>,<jats:italic>MTTP</jats:italic>,<jats:italic>SERPINA1</jats:italic>,<jats:italic>FTO</jats:italic>,<jats:italic>IL1RN</jats:italic>,<jats:italic>COBLL1</jats:italic>,<jats:italic>APOH</jats:italic>, and<jats:italic>IFI30</jats:italic>). Pleiotropy analysis showed that 61 of 77 trans-ancestry and all 17 validated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.</jats:p>
Gill D, Georgakis MK, Walker VM, et al., 2021, Mendelian randomization for studying the effects of perturbing drug targets [version 1; peer review: awaiting peer review], Wellcome Open Research, Vol: 6, Pages: 1-11
Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline.
Gill D, Georgakis M, Walker V, et al., 2021, Mendelian randomization for studying the effects of perturbing drug targets
Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline.
Maners J, Gill D, Pankratz N, et al., 2020, A Mendelian randomization of γ′ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke, Blood, Vol: 136, Pages: 3062-3069, ISSN: 0006-4971
Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ′) fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ′ fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ′ fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ′ fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ′ fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ′ fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ′ fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.
Burgess S, Smith D, Kenyon JC, et al., 2020, Lightening the viral load to lessen covid-19 severity., BMJ, Vol: 371, Pages: 1-2, ISSN: 1759-2151
Daghlas I, Gill D, 2020, Blood Pressure Modification and Life Expectancy in a General Population Mendelian Randomization Analysis, CIRCULATION-GENOMIC AND PRECISION MEDICINE, Vol: 13, Pages: 710-712, ISSN: 2574-8300
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Gill D, Arvanitis M, Carter P, et al., 2020, ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels: a Mendelian randomization study, Royal Society Open Science, Vol: 7, Pages: 1-12, ISSN: 2054-5703
Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 × 10−4) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.
Gill D, Ponsford MJ, 2020, Testing for antibodies to SARS-CoV-2, BMJ-BRITISH MEDICAL JOURNAL, Vol: 371, ISSN: 0959-535X
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Georgakis MK, Malik R, Li X, et al., 2020, Genetically downregulated interleukin-6 signaling is associated with a favorable cardiometabolic profile: a phenome-wide association study
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Interleukin-6 (IL6) signaling is a key inflammatory pathway widely implicated in the pathogenesis of multiple diseases including autoimmune, vascular, and metabolic disorders. While IL6-receptor (IL6R) inhibitors are already in use for the treatment of autoimmune diseases, their repurposing potential and safety profile is still debated.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used 7 genetic variants at the<jats:italic>IL6R</jats:italic>locus as proxies for IL6 signaling downregulation and explored their effects on 1,428 clinical outcomes in a phenome-wide association study (PheWAS) using data from the UK Biobank (339,256 unrelated individuals). Significant associations were meta-analyzed with data from the Penn Medicine (10,244 individuals) and BioMe (9,054 individuals) Biobanks for validation. We further investigated associations between genetically downregulated IL6 signaling and 366 biomarkers and endophenotypes of human disease in the UK Biobank and other phenotype-specific consortia. All associations were examined by Mendelian randomization (MR) analyses scaled to the effects of tocilizumab, a monoclonal antibody targeting IL6R.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The PheWAS-MR analyses showed significant associations with 16 clinical outcomes and 17 biomarkers following correction for multiple comparisons. Genetically downregulated IL6 signaling was associated with a lower risk of several atherosclerotic phenotypes including ischemic heart disease (OR: 0.84, 95%CI: 0.77-0.90) and abdominal aortic aneurysm (OR: 0.44, 95%CI: 0.29-0.67). We further found significant associations with lower risk of type 2 diabetes (OR: 0.80, 95%CI: 0.73-0.88), lower glycated hemoglobin A1c (HbA1c) levels (beta: &mi
Ponsford MJ, Gkatzionis A, Walker VM, et al., 2020, Cardiometabolic Traits, Sepsis, and Severe COVID-19 A Mendelian Randomization Investigation, CIRCULATION, Vol: 142, Pages: 1791-1793, ISSN: 0009-7322
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
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