Publications
313 results found
Burgess S, Gill D, 2022, Genetic evidence for vitamin D and cardiovascular disease: choice of variants is critical (Feb, ehab870, 2022), EUROPEAN HEART JOURNAL, Vol: 43, Pages: 2659-2659, ISSN: 0195-668X
Nhu NL, Tran TQB, Lip S, et al., 2022, Unravelling the Distinct Effects of Systolic and Diastolic Blood Pressure Using Mendelian Randomisation, GENES, Vol: 13
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- Citations: 3
Yuan S, Chen J, Li X, et al., 2022, Lifestyle and metabolic factors for nonalcoholic fatty liver disease: Mendelian randomization study, EUROPEAN JOURNAL OF EPIDEMIOLOGY, Vol: 37, Pages: 723-733, ISSN: 0393-2990
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- Citations: 22
Coscia C, Gill D, Benitez R, et al., 2022, Avoiding collider bias in Mendelian randomization when performing stratified analyses, EUROPEAN JOURNAL OF EPIDEMIOLOGY, Vol: 37, Pages: 671-682, ISSN: 0393-2990
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- Citations: 10
Woolf B, Gill D, 2022, TwoStepCisMR: A novel method and R package for attenuating bias in <i>cis</i>-MR
<jats:title>Abstract</jats:title><jats:p>Mendelian randomisation (MR) is an increasingly popular method for strengthening causal inference in epidemiological studies. cis-MR in particular uses genetic variants in the gene region for a genetic proxy of a drug target to provide quasi-experimental evidence for drug efficacy. A major problem for this framework is when the causal variant is correlated to another variant which effects the outcome of interest (confounding through linkage disequilibrium). Methods for correcting bias such as multivariable MR struggle in a cis setting because of the high correlation among genetic variants. Here, we therefore present an alternative method for attenuating bias which does not suffer from this problem. We have additionally developed a simple R package to facilitate the implementation of the method.</jats:p>
Moksnes MR, Graham SE, Wu K-H, et al., 2022, Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT, COMMUNICATIONS BIOLOGY, Vol: 5
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- Citations: 4
Rogne T, Burgess S, Gill D, 2022, Systemic iron status and maternal pregnancy complications: a Mendelian randomization study, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 51, Pages: 1024-1027, ISSN: 0300-5771
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- Citations: 1
Carter AR, Harrison S, Gill D, et al., 2022, Educational attainment as a modifier for the effect of polygenic scores for cardiovascular risk factors: cross-sectional and prospective analysis of UK Biobank., Int J Epidemiol, Vol: 51, Pages: 885-897
BACKGROUND: Understanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of the aetiology of educational inequalities in cardiovascular disease. METHODS: In up to 320 120 UK Biobank participants of White British ancestry (mean age = 57 years, 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. RESULTS: On the additive scale, higher educational attainment reduced genetic susceptibility to higher body mass index, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure. On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but little evidence of effect modification was found for all other traits considered. CONCLUSIONS: 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 education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to substantially explain the development of inequalities in cardiovascular risk.
Burgess S, Chirinos JA, Damrauer SM, et al., 2022, Genetically Predicted Pulse Pressure and Risk of Abdominal Aortic Aneurysm: A Mendelian Randomization Analysis, CIRCULATION-GENOMIC AND PRECISION MEDICINE, Vol: 15, ISSN: 2574-8300
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- Citations: 1
Zhao SS, Karhunen V, Morris AP, et al., 2022, ADAMTS5 as a therapeutic target for osteoarthritis: Mendelian randomisation study, ANNALS OF THE RHEUMATIC DISEASES, Vol: 81, Pages: 903-904, ISSN: 0003-4967
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- Citations: 3
Vujkovic M, Ramdas S, Lorenz KM, et al., 2022, A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation, NATURE GENETICS, Vol: 54, Pages: 761-+, ISSN: 1061-4036
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- Citations: 26
Page C, Smith D, Rajasundaram S, et al., 2022, Translating pharmacological developments into clinical practice: case study of Ronapreve for COVID-19, Publisher: SPRINGER HEIDELBERG, Pages: S68-S69, ISSN: 0031-6970
Kamiza AB, Toure SM, Vujkovic M, et al., 2022, Transferability of genetic risk scores in African populations, NATURE MEDICINE, Vol: 28, Pages: 1163-+, ISSN: 1078-8956
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- Citations: 12
Roychowdhury T, Klarin D, Levin MG, et al., 2022, Multi-ancestry GWAS deciphers genetic architecture of abdominal aortic aneurysm and highlights<i>PCSK9</i>as a therapeutic target
<jats:title>Summary</jats:title><jats:p>Abdominal aortic aneurysm (AAA) is a common disease with significant heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 144 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis was able to explain AAA beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in the pathogenesis of AAA. We further integrated functional data to elucidate expression of genes associated with AAA. These genes also indicate crossover between the development of AAA and other monogenic aortopathies, particularly via TGF-β signaling pathways. Motivated by the strong evidence for the role of lipid levels in AAA by PheWAS, we identified therapeutic opportunities using Mendelian Randomization and, in pre-clinical studies, we demonstrated that<jats:italic>PCSK9</jats:italic>inhibition in mice prevented the development of AAA.</jats:p>
Burgess S, Gill D, 2022, Genetic evidence for vitamin D and cardiovascular disease: choice of variants is critical, EUROPEAN HEART JOURNAL, Vol: 43, Pages: 1740-1742, ISSN: 0195-668X
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- Citations: 9
Zuber V, Grinberg NF, Gill D, et al., 2022, Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 109, Pages: 767-782, ISSN: 0002-9297
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- Citations: 35
Korte N, Ilkan Z, Pearson CL, et al., 2022, The Ca<SUP>2+</SUP>-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia, JOURNAL OF CLINICAL INVESTIGATION, Vol: 132, ISSN: 0021-9738
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- Citations: 23
Larsson SC, Woolf B, Gill D, 2022, Plasma Caffeine Levels and Risk of Alzheimer's Disease and Parkinson's Disease: Mendelian Randomization Study, NUTRIENTS, Vol: 14
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- Citations: 10
Fang S, Yarmolinsky J, Gill D, et al., 2022, Genetically proxied PCSK9 inhibition provides indication of lower prostate cancer risk: a Mendelian randomization study
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Prostate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomization (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c lowering drug targets on risk of PrCa.</jats:p></jats:sec><jats:sec><jats:title>Methods and Findings</jats:title><jats:p>Single-nucleotide polymorphisms (SNPs) in and around <jats:italic>HMGCR, NPC1L1</jats:italic> and <jats:italic>PCSK9</jats:italic> genes associated with LDL-c (P<5×10<jats:sup>−8</jats:sup>) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N=173,082) were used to proxy the therapeutic inhibition of these targets. Association estimates for the risk of total, advanced and early-onset PrCa were obtained from the PRACTICAL consortium. Replication was performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N=201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI) and testosterone).</jats:p><jats:p>Applying MR using the inverse-variance weighted approach accounting for genetic correlations between instruments provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrC
Stacey D, Chen L, Stanczyk PJ, et al., 2022, Elucidating mechanisms of genetic cross-disease associations at the <i>PROCR</i> vascular disease locus (vol 13, 1222, 2022), NATURE COMMUNICATIONS, Vol: 13
Soremekun O, Karhunen V, He Y, et al., 2022, Lipid traits and type 2 diabetes risk in African ancestry individuals: a Mendelian Randomization study, EBioMedicine, Vol: 78, ISSN: 2352-3964
BACKGROUND: Dyslipidaemia is highly prevalent in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have sought to disentangle the causal relationship between dyslipidaemia and T2DM liability. However, conventional observational studies are vulnerable to confounding. Mendelian Randomization (MR) studies (which address this bias) on lipids and T2DM liability have focused on European ancestry individuals, with none to date having been performed in individuals of African ancestry. We therefore sought to use MR to investigate the causal effect of various lipid traits on T2DM liability in African ancestry individuals. METHODS: Using univariable and multivariable two-sample MR, we leveraged summary-level data for lipid traits and T2DM liability from the African Partnership for Chronic Disease Research (APCDR) (N = 13,612, 36.9% men) and from African ancestry individuals in the Million Veteran Program (Ncases = 23,305 and Ncontrols = 30,140, 87.2% men), respectively. Genetic instruments were thus selected from the APCDR after which they were clumped to obtain independent instruments. We used a random-effects inverse variance weighted method in our primary analysis, complementing this with additional sensitivity analyses robust to the presence of pleiotropy. FINDINGS: Increased genetically proxied low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were associated with increased T2DM liability in African ancestry individuals (odds ratio (OR) [95% confidence interval, P-value] per standard deviation (SD) increase in LDL-C = 1.052 [1.000 to 1.106, P = 0.046] and per SD increase in TC = 1.089 [1.014 to 1.170, P = 0.019]). Conversely, increased genetically proxied high-density lipoprotein cholesterol (HDL-C) was associated with reduced T2DM liability (OR per SD increase in HDL-C = 0.915 [0.843 to 0.993, P = 0.033]). The OR on T2DM per SD increase i
Grant AJ, Gill D, Kirk PDW, et al., 2022, A noise-augmented directional clustering approach for identifying distinct mechanisms underlying genetic associations, 50th European Mathematical Genetics Meeting (EMGM), Publisher: KARGER, Pages: 23-24, ISSN: 0001-5652
Pazoki R, Vujkovic M, Elliott J, et al., 2022, Genome-wide association study and replication of liver enzyme loci, Publisher: SPRINGERNATURE, Pages: 47-48, ISSN: 1018-4813
Carter AR, Gill D, Smith GD, et al., 2022, Cross-sectional analysis of educational inequalities in primary prevention statin use in UK Biobank, HEART, Vol: 108, Pages: 536-542, ISSN: 1355-6037
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- Citations: 1
Patel A, Gill D, Newcombe P, et al., 2022, Conditional inference in <i>cis</i>-Mendelian randomization using weak genetic factors, Publisher: WILEY, Pages: 20-20, ISSN: 0006-341X
Xie J, Prats-Uribe A, Feng Q, et al., 2022, Venous Thromboembolism in Ambulatory Covid-19 patients: Clinical and Genetic Determinants
<jats:p>BackgroundSubstantial evidence suggests that severe Covid-19 leads to an increased risk of Venous Thromboembolism (VTE). We aimed to quantify the risk of VTE associated with ambulatory Covid-19, study the potential protective role of vaccination, and establish key clinical and genetic determinants of post-Covid VTE.MethodsWe analyzed a cohort of ambulatory Covid-19 patients from UK Biobank, and compared their 30-day VTE risk with propensity-score-matched non-infected participants. We fitted multivariable models to study the associations between age, sex, ethnicity, socio-economic status, obesity, vaccination status and inherited thrombophilia with post-Covid VTE.ResultsOverall, VTE risk was nearly 20-fold higher in Covid-19 vs matched non-infected participants (hazard ratio [HR] 19.49, 95% confidence interval [CI] 11.50 to 33.05). However, the risk was substantially attenuated amongst the vaccinated (HR: 2.79, 95% CI 0.82 to 9.54). Older age, male sex, and obesity were independently associated with higher risk, with adjusted HRs of 2.00 (1.61 to 2.47) per 10 years, 1.66 (1.28 to 2.15), and 1.85 (1.29 to 2.64), respectively. Further, inherited thrombophilia led to an HR 2.05, 95% CI 1.15 to 3.66.ConclusionsAmbulatory Covid-19 was associated with a striking 20-fold increase in incident VTE, but no elevated risk after breakthrough infection in the fully vaccinated. Older age, male sex, and obesity were clinical determinants of Covid-19-related VTE. Additionally, inherited thrombophilia doubled risk further, comparable to the effect of 10-year ageing. These findings reinforce the need for vaccination, and call for targeted strategies to prevent VTE during outpatient care of Covid-19</jats:p>
Stacey D, Chen L, Stanczyk P, et al., 2022, Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus, Nature Communications, Vol: 13, ISSN: 2041-1723
Many individual genetic risk loci have been associated with multiple common human diseases. However, themolecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal themolecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) riskbut higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variantat the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitroexperimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C throughendothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CADthrough anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides aframework to reveal the mechanisms underlying similar cross-phenotype associations.
Yuan S, Gill D, Giovannucci EL, et al., 2022, Obesity, type 2 diabetes, lifestyle factors, and risk of gallstone disease: a Mendelian randomization investigation, Clinical Gastroenterology and Hepatology, Vol: 20, Pages: e529-e537, ISSN: 1542-3565
BACKGROUND & AIMS: Obesity, type 2 diabetes, and lifestyle factors (cigarette smoking, alcohol drinking, and coffee consumption) have been associated with the risk of developing gallstone disease in observational studies, but whether these associations are causal is undetermined. We conducted a Mendelian randomization study to assess these associations. METHODS: Genetic instruments associated with the exposures at the genome-wide significance (p < 5×10-8) level were selected from corresponding genome-wide associations studies (n=224 459 to 1 232 091 individuals). Summary-level data for gallstone disease were obtained from the UK Biobank (10 520 cases and 350 674 non-cases) and FinnGen consortium (11 675 cases and 121 348 non-cases). Univariable and multivariable Mendelian randomization analyses were conducted. Results from UK Biobank and FinnGen were combined using fixed-effects meta-analysis. RESULTS: The odds ratios were 1.63 (95% confidence interval (CI), 1.49, 1.79) for one standard deviation (SD) increase in body mass index, 1.81 (95% CI, 1.60, 2.05) for one SD increase in waist circumference, 1.13 (95% CI, 1.09, 1.17) for one unit increase in the log-odds ratio of type 2 diabetes and 1.25 (95% CI, 1.16, 1.34) for one SD increase in prevalence of smoking initiation. The associations for body mass index and type 2 diabetes persisted after mutual adjustment. Genetically predicted coffee consumption was inversely associated with gallstone disease after adjustment for body mass index and smoking (odds ratio per 50% increase 0.44, 95% CI, 0.21, 0.91). There was no association with alcohol consumption. CONCLUSIONS: This study supports independent causal roles of obesity, type 2 diabetes, and smoking in gallstone disease.
Chikowore T, Ekoru K, Vujkovi M, et al., 2022, Polygenic Prediction of Type 2 Diabetes in Africa, DIABETES CARE, Vol: 45, Pages: 717-723, ISSN: 0149-5992
Korte N, Ilkan Z, Pearson C, et al., 2022, The Ca<sup>2+</sup>-gated Cl<sup>-</sup> channel TMEM16A amplifies capillary pericyte contraction reducing cerebral blood flow after ischemia
<jats:title>ABSTRACT</jats:title><jats:p>Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca<jats:sup>2+</jats:sup> concentration ([Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>) in pericytes activates chloride efflux through the Ca<jats:sup>2+</jats:sup>-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplifies the pericyte [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slows the ischemia-evoked pericyte [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> rise, capillary constriction and pericyte death, reduces neutrophil stalling and improves cerebrovascular reperfusion. Genetic analysis implicates altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function, and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer’s disease and vascular dementia.</jats:p>
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