Publications
309 results found
Ryan D, Karhunen V, Su B, et al., 2023, Genetic evidence for protective effects of angiotensin converting enzyme against Alzheimer's disease but not other neurodegenerative diseases, Pharmacology Annual Meeting, Publisher: WILEY, Pages: 565-567, ISSN: 0007-1188
Bakker MK, van Straten T, Chong M, et al., 2023, Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk: Mendelian Randomization and Colocalization Study, STROKE, Vol: 54, Pages: 208-216, ISSN: 0039-2499
Fang SM, Yarmolinsky J, Gill DR, et al., 2023, Association between genetically proxied PCSK9 inhibition and prostate cancer risk: A Mendelian randomisation study, PLOS MEDICINE, Vol: 20, ISSN: 1549-1277
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- Citations: 3
Larsson SC, Woolf B, Gill D, 2023, Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study., BMJ Med, Vol: 2, Pages: 1-8
OBJECTIVE: To investigate the potential causal effects of long term plasma caffeine concentrations on adiposity, type 2 diabetes, and major cardiovascular diseases. DESIGN: Two sample mendelian randomisation study. SETTING: Genome-wide association study summary data for associations of two single nucleotide polymorphisms associated with plasma caffeine at the genome-wide significance threshold (rs2472297 near the CYP1A2 gene and rs4410790 near the AHR gene) and their association with the outcomes. PARTICIPANTS: Primarily individuals of European ancestry participating in cohorts contributing to genome-wide association study consortia. MAIN OUTCOME MEASURES: Outcomes studied were body mass index, whole body fat mass, whole body fat-free mass, type 2 diabetes, ischaemic heart disease, atrial fibrillation, heart failure, and stroke. RESULTS: Higher genetically predicted plasma caffeine concentrations were associated with lower body mass index (beta -0.08 standard deviation (SD) (95% confidence interval -0.10 to -0.06), where 1 SD equals about 4.8 kg/m2 in body mass index, for every standard deviation increase in plasma caffeine) and whole body fat mass (beta -0.06 SD (-0.08 to -0.04), 1 SD equals about 9.5 kg; P<0.001) but not fat-free mass (beta -0.01 SD (-0.02 to -0.00), 1 SD equals about 11.5 kg; P=0.17). Higher genetically predicted plasma caffeine concentrations were associated with a lower risk of type 2 diabetes in two consortia (FinnGen and DIAMANTE), with a combined odds ratio of 0.81 ((95% confidence interval 0.74 to 0.89); P<0.001). Approximately half (43%; 95% confidence interval 30% to 61%) of the effect of caffeine on type 2 diabetes was estimated to be mediated through body mass index reduction. No strong associations were reported between genetically predicted plasma caffeine concentrations and a risk of any of the studied cardiovascular diseases. CONCLUSIONS: Higher plasma caffeine concentrations might reduce adiposity and risk of type 2 diabetes.
Karhunen V, Gill D, Huang J, et al., 2023, The interplay between inflammatory cytokines and cardiometabolic disease: bi-directional mendelian randomisation study., BMJ Med, Vol: 2
OBJECTIVE: To leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets. DESIGN: Bi-directional Mendelian randomisation study. SETTING: Genome-wide association studies from three Finnish cohorts (Northern Finland Birth Cohort 1966, Young Finns Study, or FINRISK study), and genetic association summary statistics pooled from observational studies for expression quantitative trait loci and cardiometabolic traits. PARTICIPANTS: Data for 47 circulating cytokines in 13 365 individuals from genome-wide association studies, summary statistic data for up to 21 735 individuals on circulating cytokines, summary statistic gene expression data across 49 tissues in 838 individuals, and summary statistic data for up to 1 320 016 individuals on cardiometabolic traits. INTERVENTIONS: Relations between circulating cytokines and cardiovascular, anthropometric, lipid, or glycaemic traits (coronary artery disease, stroke, type 2 diabetes mellitus, body mass index, waist circumference, waist to hip ratio, systolic blood pressure, glycated haemoglobin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, triglycerides, C reactive protein, glucose, fasting insulin, and lifetime smoking). MAIN OUTCOME METHODS: Genetic instrumental variables that are biologically plausible for the circulating cytokines were generated. The effects of cardiometabolic risk factors on concentrations of circulating cytokines, circulating cytokines on other circulating cytokines, and circulating cytokines on cardiometabolic outcomes were investigated. RESULTS: Genetic evidence (mendelian randomisation P<0.0011) suggests that higher body mass index, waist circumference, smoking, higher concentrations of lipids, and systolic blood pressure increase circulating concentrations of several inflammatory cytokines and C reactive protein. Evi
Zagkos L, Dib M-J, Pinto R, et al., 2022, Associations of genetically predicted fatty acid levels across the phenome: a mendelian randomisation study, PLoS Medicine, Vol: 19, ISSN: 1549-1277
BACKGROUND: Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes. METHODS AND FINDINGS: The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.
Yuan S, Chen J, Vujkovic M, et al., 2022, The effects of metabolic traits, lifestyle factors and pharmacological interventions on liver fat: a mendelian randomisation study, BMJ Medicine, Vol: 1, ISSN: 2754-0413
Objective: To investigate the effects of metabolic traits, lifestyle factors, and drug interventions on liver fat using the mendelian randomisation paradigm.Design: Mendelian randomisation study.Setting: Publicly available summary level data from genome-wide association studies.Participants: Genome-wide association studies of 32 974 to 1 407 282 individuals who were predominantly of European descent.Exposures: Genetic variants predicting nine metabolic traits, six lifestyle factors, four lipid lowering drug targets, three antihypertensive drug targets, and genetic association estimates formagnetic resonance imaging measured liver fat.Main outcome measures: Mendelian randomisation analysis was used to investigate the effects of these exposures on liver fat, incorporating sensitivity analyses that relaxed the requisite modelling assumptions.Results: Genetically predicted liability to obesity, type 2 diabetes, elevated blood pressure, elevated triglyceride levels, cigarette smoking, and sedentary time watching television were associated with higher levels of liver fat. Genetically predicted lipid lowering drug effects were not associated with liver fat; however, β blocker and calcium channel blocker antihypertensive drug effects were associated with lower levels of liver fat.Conclusion: These analyses provide evidence of a causal effect of various metabolic traits, lifestyle factors, and drug targets on liver fat. The findings complement existing epidemiological associations, further provide mechanistic insight, and potentially supports a role for drug interventions in reducing the burden of hepatic steatosis and related disease. Further clinical study is now warranted to investigate the relevance of these genetic analyses for patient care.
Zhang Z, Wang M, Gill D, et al., 2022, Genetically Predicted Smoking and Alcohol Consumption and Functional Outcome After Ischemic Stroke, NEUROLOGY, Vol: 99, Pages: E2693-E2698, ISSN: 0028-3878
Yuan S, Wang L, Sun J, et al., 2022, Genetically predicted sex hormone levels and health outcomes: phenome-wide Mendelian randomization investigation, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 51, Pages: 1931-1942, ISSN: 0300-5771
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- Citations: 9
Soremekun O, Slob EAW, Burgess S, et al., 2022, Genetically Predicted Lipid Traits, Diabetes Liability, and Carotid Intima-Media Thickness in African Ancestry Individuals: A Mendelian Randomization Study, CIRCULATION-GENOMIC AND PRECISION MEDICINE, Vol: 15, Pages: 608-610, ISSN: 2574-8300
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- Citations: 1
Gill D, Pan Y, Lash JP, et al., 2022, Revisiting the Effects of Blood Pressure on Kidney Function: New Insights From a Mendelian Randomization Analysis, HYPERTENSION, Vol: 79, Pages: 2682-2684, ISSN: 0194-911X
Xie J, Prats-Uribe A, Maranon MG, et al., 2022, Genetic risk and incident venous thromboembolism in middle-aged and older adults following COVID-19 vaccination, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 20, Pages: 2887-2895, ISSN: 1538-7933
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- Citations: 1
Dib M-J, Ahmadi KR, Zagkos L, et al., 2022, Associations of genetically predicted vitamin B12 status across the pohenome, Nutrients, Vol: 14, ISSN: 2072-6643
Variation in vitamin B12 levels has been associated with a range of diseases across the life-course, the causal nature of which remains elusive. We aimed to interrogate genetically predicted vitamin B12 status in relation to a plethora of clinical outcomes available in the UK Biobank. Genome-wide association study (GWAS) summary data obtained from a Danish and Icelandic cohort of 45,576 individuals were used to identify 8 genetic variants associated with vitamin B12 levels, serving as genetic instruments for vitamin B12 status in subsequent analyses. We conducted a Mendelian randomisation (MR)-phenome-wide association study (PheWAS) of vitamin B12 status with 945 distinct phenotypes in 439,738 individuals from the UK Biobank using these 8 genetic instruments to proxy alterations in vitamin B12 status. We used external GWAS summary statistics for replication of significant findings. Correction for multiple testing was taken into consideration using a 5% false discovery rate (FDR) threshold. MR analysis identified an association between higher genetically predicted vitamin B12 status and lower risk of vitamin B deficiency (including all B vitamin deficiencies), serving as a positive control outcome. We further identified associations between higher genetically predicted vitamin B12 status and a reduced risk of megaloblastic anaemia (OR = 0.35, 95% CI: 0.20–0.50) and pernicious anaemia (0.29, 0.19–0.45), which was supported in replication analyses. Our study highlights that higher genetically predicted vitamin B12 status is potentially protective of risk of vitamin B12 deficiency associated with pernicious anaemia diagnosis, and reduces risk of megaloblastic anaemia. The potential use of genetically predicted vitamin B12 status in disease diagnosis, progression and management remains to be investigated.
Giontella A, Lotta LA, Baras A, et al., 2022, Calcium, Its Regulatory Hormones, and Their Causal Role on Blood Pressure: A Two-Sample Mendelian Randomization study, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 107, Pages: 3080-3085, ISSN: 0021-972X
Ryan DK, Karhunen V, Su B, et al., 2022, Genetic evidence for protective effects of angiotensin converting enzyme against Alzheimer's disease but not other neurodegenerative diseases in European populations, Neurology Genetics, Vol: 8, ISSN: 2376-7839
Background and Objectives: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases.Methods: We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk in people of European ancestry. We further investigated whether any effect of ACE expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm.Results: There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk in people of European ancestry. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that ACE expression affected risk of other neurodegenerative traits.Discussion: Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease.
Yuan S, Karhunen V, Larsson S, et al., 2022, Anthropometric Traits and Risk of Mitral Valve Prolapse: A Mendelian Randomization Study, CIRCULATION-GENOMIC AND PRECISION MEDICINE, Vol: 15, Pages: 473-475, ISSN: 2574-8300
Zhao SS, Rajasundaram S, Karhunen V, et al., 2022, Sodium-glucose cotransporter 1 inhibition and gout: Mendelian randomisation study, SEMINARS IN ARTHRITIS AND RHEUMATISM, Vol: 56, ISSN: 0049-0172
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- Citations: 2
Zhao SS, Gill D, 2022, Genetically proxied IL-6 receptor inhibition and risk of polymyalgia rheumatica, ANNALS OF THE RHEUMATIC DISEASES, Vol: 81, Pages: 1480-1482, ISSN: 0003-4967
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- Citations: 2
Batool F, Patel A, Gill D, et al., 2022, Disentangling the effects of traits with shared clustered genetic predictors using multivariable Mendelian randomization, GENETIC EPIDEMIOLOGY, Vol: 46, Pages: 415-429, ISSN: 0741-0395
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- Citations: 1
Ardissino M, Rajasundaram S, Reddy R, et al., 2022, Safety of beta-blocker and calcium channel blocker antihypertensive drugs in pregnancy: a Mendelian randomization study, BMC Medicine, Vol: 20, ISSN: 1741-7015
Background: Beta-blocker (BB) and calcium channel blocker (CCB)antihypertensive drugs are commonly used in pregnancy. However, data on theirrelative impact on maternal and fetal outcomes are limited. We leveraged geneticvariants mimicking BB and CCB antihypertensive drugs to investigate their effects onrisk of pre-eclampsia, gestational diabetes and birthweight using the Mendelianrandomization paradigm.Methods: Genetic association estimates for systolic blood pressure (SBP) wereextracted from summary data of a genome-wide association study (GWAS) on757,601 participants. Uncorrelated single-nucleotide polymorphisms (SNPs)associated with SBP (p<5x10-8) in BB and CCB drug target gene regions wereselected as proxies for drug target perturbation. Genetic association estimates forthe outcomes were extracted from GWASs on 4,743 cases and 136,325 controls(women without a hypertensive disorder in pregnancy) for pre-eclampsia oreclampsia, 7,676 cases and 130,424 controls (women without any pregnancy-relatedmorbidity) for gestational diabetes, and 155,202 women (who have given birth atleast once) for birthweight of the first child. All studies were in European ancestrypopulations. Mendelian randomization estimates were generated using the twosample inverse-variance weighted model.Results: Although not reaching the conventional threshold for statistical significance,genetically-proxied BB was associated with reduced risk of pre-eclampsia (OR per10mmHg SBP reduction 0.27, 95%CI 0.06-1.19, p=0.08) and increased risk ofgestational diabetes (OR per 10mmHg SBP reduction 2.01, 95%CI 0.91-4.42,p=0.08), and significantly associated with lower birthweight of first child (beta per 10mmHg SBP reduction -0.27, 95%CI -0.39 to -0.15, p=1.90x10-5). Geneticallyproxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR0.62, 95%CI 0.43-0.89, p=9.33x10-3), and was not associated with gestationaldiabetes (OR 1.05, 95% CI 0.76-1.45, p=0.76) or changes in birthweight of first
Cohen JB, Mitchell GF, Gill D, et al., 2022, Arterial Stiffness and Diabetes Risk in Framingham Heart Study and UK Biobank, CIRCULATION RESEARCH, Vol: 131, Pages: 545-554, ISSN: 0009-7330
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- Citations: 9
Xie J, Strauss VY, Prats-Uribe A, et al., 2022, Genetic risk and incident venous thromboembolism in middle-aged and older adults following COVID-19 vaccination, PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Vol: 31, Pages: 118-118, ISSN: 1053-8569
Woolf B, Zagkos L, Gill D, 2022, TwoStepCisMR: A Novel Method and R Package for Attenuating Bias in <i>cis</i>-Mendelian Randomization Analyses, GENES, Vol: 13
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- Citations: 2
Xie J, Prats-Uribe A, Feng Q, et al., 2022, Clinical and genetic risk factors for acute incident venous Thromboembolism in ambulatory patients with COVID-19., JAMA Internal Medicine, Vol: 182, Pages: 1063-1070, ISSN: 2168-6106
Importance: The risk of venous thromboembolism (VTE) in ambulatory COVID-19 is controversial. In addition, the association of vaccination with COVID-19-related VTE and relevant clinical and genetic risk factors remain to be elucidated. Objective: To quantify the association between ambulatory COVID-19 and short-term risk of VTE, study the potential protective role of vaccination, and investigate clinical and genetic risk factors for post-COVID-19 VTE. Design, Setting, and Participants: This population-based cohort study of patients with COVID-19 from UK Biobank included participants with SARS-CoV-2 infection that was confirmed by a positive polymerase chain test reaction result between March 1, 2020, and September 3, 2021, who were then propensity score matched to COVID-19-naive people during the same period. Participants with a history of VTE who used antithrombotic drugs (1 year before index dates) or tested positive in hospital were excluded. Exposures: First infection with SARS-CoV-2, age, sex, ethnicity, socioeconomic status, obesity, vaccination status, and inherited thrombophilia. Main Outcomes and Measures: The primary outcome was a composite VTE, including deep vein thrombosis or pulmonary embolism, which occurred 30 days after the infection. Hazard ratios (HRs) with 95% CIs were calculated using cause-specific Cox models. Results: In 18 818 outpatients with COVID-19 (10 580 women [56.2%]; mean [SD] age, 64.3 [8.0] years) and 93 179 matched uninfected participants (52 177 women [56.0%]; mean [SD] age, 64.3 [7.9] years), the infection was associated with an increased risk of VTE in 30 days (incidence rate of 50.99 and 2.37 per 1000 person-years for infected and uninfected people, respectively; HR, 21.42; 95% CI, 12.63-36.31). However, risk was substantially attenuated among the fully vaccinated (HR, 5.95; 95% CI, 1.82-19.5; interaction P = .02). In patients with COVID-19, older age, male sex, and obesity were independently associated with highe
Gill D, Vujkovic M, 2022, The Potential of Genetic Data for Prioritizing Drug Repurposing Efforts, NEUROLOGY, Vol: 99, Pages: 267-268, ISSN: 0028-3878
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- Citations: 2
Georgakis MK, Malik R, Richardson TG, et al., 2022, Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups, BMC MEDICINE, Vol: 20, ISSN: 1741-7015
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- Citations: 7
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
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