Publications
313 results found
Gill D, Woolf B, Zagkos L, et al., 2023, The cardiovascular efficacy of lipid-lowering drug targets is not entirely explained by apolipoprotein B reduction: Mendelian randomization evidence, Circulation: Genomic and Precision Medicine, Vol: 16, Pages: 490-492, ISSN: 2574-8300
Woolf B, Cronje HT, Zagkos L, et al., 2023, Appraising the causal relationship between plasma caffeine levels and neuropsychiatric disorders through Mendelian randomization, BMC MEDICINE, Vol: 21, ISSN: 1741-7015
Burgess S, Davey Smith G, Davies NM, et al., 2023, Guidelines for performing Mendelian randomization investigations: update for summer 2023, Wellcome Open Research, Vol: 4, Pages: 186-186
<ns3:p>This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into ten sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), extensions and additional analyses, data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 24 months.</ns3:p>
Jiang T, Gill D, Butterworth AS, et al., 2023, An empirical investigation into the impact of winner's curse on estimates from Mendelian randomization, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 52, Pages: 1209-1219, ISSN: 0300-5771
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- Citations: 8
Kraaijenhof JM, Opstal TSJ, Cornel JH, et al., 2023, Effect of PCSK9 Inhibition on the Plasma Proteome: A SPIRE SubStudy, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 43, Pages: 1595-1597, ISSN: 1079-5642
Giontella A, Zagkos L, Geybels M, et al., 2023, Renoprotective effects of genetically proxied fibroblast growth factor 21: Mendelian randomization, proteome-wide and metabolome-wide association study, METABOLISM-CLINICAL AND EXPERIMENTAL, Vol: 145, ISSN: 0026-0495
Yarmolinsky J, Bouras E, Constantinescu A, et al., 2023, Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis, DIABETOLOGIA, Vol: 66, Pages: 1481-1500, ISSN: 0012-186X
Woolf B, Sallis HM, Munafo MR, et al., 2023, Deriving GWAS summary estimates for paternal smoking in UK biobank: a GWAS by subtraction, BMC RESEARCH NOTES, Vol: 16
Woolf B, Gill D, Sallis H, et al., 2023, The UK BiLEVE and Mendelian randomisation: using multivariable instrumental variables to address "damned if you, damned if you don't" adjustment problems, BMC RESEARCH NOTES, Vol: 16
Yuan S, Li Y, Wang L, et al., 2023, Deciphering the genetic architecture of atrial fibrillation offers insights into disease prediction, pathophysiology and downstream sequelae., medRxiv
AIMS: The study aimed to discover novel genetic loci for atrial fibrillation (AF), explore the shared genetic etiologies between AF and other cardiovascular and cardiometabolic traits, and uncover AF pathogenesis using Mendelian randomization analysis. METHODS AND RESULTS: We conducted a genome-wide association study meta-analysis including 109,787 AF cases and 1,165,920 controls of European ancestry and identified 215 loci, among which 91 were novel. We performed Genomic Structural Equation Modeling analysis between AF and four cardiovascular comorbidities (coronary artery disease, ischemic stroke, heart failure, and vneous thromboembolism) and found 189 loci shared across these diseases as well as a universal genetic locus shared by atherosclerotic outcomes (i.e., rs1537373 near CDKN2B). Three genetic loci (rs10740129 near JMJD1C, rs2370982 near NRXN3, and rs9931494 near FTO) were associated with AF and cardiometabolic traits. A polygenic risk score derived from this genome-wide meta-analysis was associated with AF risk (odds ratio 2.36, 95% confidence interval 2.31-2.41 per standard deviation increase) in the UK biobank. This score, combined with age, sex, and basic clinical features, predicted AF risk (AUC 0.784, 95% CI 0.781-0.787) in Europeans. Phenome-wide association analysis of the polygenic risk score identified many AF-related comorbidities of the circulatory, endocrine, and respiratory systems. Phenome-wide and multi-omic Mendelian randomization analyses identified associations of blood lipids and pressure, diabetes, insomnia, obesity, short sleep, and smoking, 27 blood proteins, one gut microbe (genus.Catenibacterium), and 11 blood metabolites with risk to AF. CONCLUSIONS: This genome-wide association study and trans-omic Mendelian randomization analysis provides insights into disease risk prediction, pathophysiology and downstream sequelae.
Zuber V, Lewin A, Levin MG, et al., 2023, Multi-response Mendelian randomization: Identification of shared and distinct exposures for multimorbidity and multiple related disease outcomes, American Journal of Human Genetics, Vol: 110, Pages: 1177-1199, ISSN: 0002-9297
The existing framework of Mendelian randomization (MR) infers the causal effect of one or multiple exposures on one single outcome. It is not designed to jointly model multiple outcomes, as would be necessary to detect causes of more than one outcome and would be relevant to model multimorbidity or other related disease outcomes. Here, we introduce multi-response Mendelian randomization (MR2), an MR method specifically designed for multiple outcomes to identify exposures that cause more than one outcome or, conversely, exposures that exert their effect on distinct responses. MR2 uses a sparse Bayesian Gaussian copula regression framework to detect causal effects while estimating the residual correlation between summary-level outcomes, i.e., the correlation that cannot be explained by the exposures, and vice versa. We show both theoretically and in a comprehensive simulation study how unmeasured shared pleiotropy induces residual correlation between outcomes irrespective of sample overlap. We also reveal how non-genetic factors that affect more than one outcome contribute to their correlation. We demonstrate that by accounting for residual correlation, MR2 has higher power to detect shared exposures causing more than one outcome. It also provides more accurate causal effect estimates than existing methods that ignore the dependence between related responses. Finally, we illustrate how MR2 detects shared and distinct causal exposures for five cardiovascular diseases in two applications considering cardiometabolic and lipidomic exposures and uncovers residual correlation between summary-level outcomes reflecting known relationships between cardiovascular diseases.
Soremekun O, Musanabaganwa C, Uwineza A, et al., 2023, A Mendelian randomization study of genetic liability to post-traumatic stress disorder and risk of ischemic stroke, TRANSLATIONAL PSYCHIATRY, Vol: 13, ISSN: 2158-3188
Daghlas I, Gill D, 2023, Leveraging genetic predictors of factor XI levels to anticipate results from clinical trials, European Journal of Neurology, Vol: 30, Pages: 2112-2116, ISSN: 1351-5101
BACKGROUND: Factor XI (FXI) is a promising therapeutic target for the prevention of thrombotic disease without increasing bleeding risk. METHODS: We performed Mendelian randomization (MR) analyses to investigate the association of genetically predicted reductions in FXI levels with risk of venous thromboembolism, ischemic stroke, bleeding outcomes, and lifespan. RESULTS: Genetically predicted reductions in FXI levels were associated with lower risk of ischemic stroke (odds ratio per 1 standard deviation (SD) lower serum FXI 0.90, 95% confidence interval 0.87-0.93, p = 1.59 × 10-11 ), and venous thromboembolism (0.54, 0.49-0.59, p = 2.13 × 10-39 ) but did not associate with increased bleeding risk (p > 0.16). Genetically predicted reductions in serum FXI levels associated with longer lifespan (0.37 years per 1 SD lower serum FXI, 0.13-0.61, p = 0.003). CONCLUSIONS: These genetic data support FXI as a potentially efficacious and safe therapeutic target and anticipate positive results from ongoing phase 3 clinical trials.
Daghlas I, Nassan M, Gill D, 2023, Genetically proxied lean mass and risk of Alzheimer’s disease: a Mendelian randomization study, BMJ Medicine, Vol: 2, Pages: 1-9, ISSN: 2754-0413
Objectives – To examine whether genetically proxied lean mass is associated with risk of Alzheimer’s disease.Design – Two-sample Mendelian randomization (MR) study.Setting – The UK Biobank study and genome-wide association study meta-analyses of Alzheimer’s disease (AD) and intelligence.Participants – Summary-level genetic data from 1) 450,243 UK Biobank participants with impedance measures of lean mass and fat mass, 2) an independent sample of 21,982 cases of AD and 41,944 controls without Alzheimer’s disease, 3) a replication sample of 7,329 cases of AD and 252,879 controls, and 4) 269,867 individuals partaking in a genome-wide association study of intelligence.Exposure – Genetic variants proxying variation in lean mass.Main outcome measures – Clinically diagnosed Alzheimer’s disease.Results - A one-standard deviation increase in genetically proxied appendicular lean mass (ALM) was associated with a 12% reduced risk of Alzheimer’s disease (odds ratio 0.88, 95% confidence interval 0.82-0.95, P=5x10-4). This finding was replicated in an independent AD cohort (0.89, 0.81-0.99, P=0.03) and was consistent in sensitivity analyses more robust to the inclusion of pleiotropic variants. Adjusting for potential mediation through genetically proxied intelligence did not attenuate the effect of ALM on AD. Higher genetically proxied ALM was also associated with increased intelligence (standard deviation increase in intelligence per standard deviation increase in ALM 0.09, 95% confidence interval 0.06-0.11, P=2.09x10-4), and adjusting for potential mediation through genetically liability to AD did not attenuate this association. We found similar results for the outcomes of AD and intelligence when using the exposures of genetically proxied trunk lean mass and whole-body lean mass respectively, adjusted for genetically proxied fat mass.Conclusions – These findings support that lean mass as a possible modifiab
Rogers M, Gill D, Ahlqvist E, et al., 2023, Genetically proxied impaired GIPR signaling and risk of 6 cancers, ISCIENCE, Vol: 26
Cronje HT, Gill D, 2023, Role of Clonal Hematopoiesis of Indeterminant Potential-Related Germline <i>TET2</i> Variation in Inflammation and Cardiovascular Disease Risk: A Mendelian Randomization Study, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 43, Pages: E227-E229, ISSN: 1079-5642
Wang M, Zhang Z, Liu D, et al., 2023, Soluble adhesion molecules and functional outcome after ischemic stroke: A Mendelian randomization study, JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, Vol: 32, ISSN: 1052-3057
Karageorgiou V, Gill D, Bowden J, et al., 2023, Sparse dimensionality reduction approaches in Mendelian randomization with highly correlated exposures., eLife, Vol: 12, Pages: 1-35, ISSN: 2050-084X
Multivariable Mendelian randomization (MVMR) is an instrumental variable technique that generalizes the MR framework for multiple exposures. Framed as a linear regression problem, it is subject to the pitfall of multi-collinearity. The bias and efficiency of MVMR estimates thus depends heavily on the correlation of exposures. Dimensionality reduction techniques such as principal component analysis (PCA) provide transformations of all the included variables that are effectively uncorrelated. We propose the use of sparse PCA (sPCA) algorithms that create principal components of subsets of the exposures with the aim of providing more interpretable and reliable MR estimates. The approach consists of three steps. We first apply a sparse dimension reduction method and transform the variant-exposure summary statistics to principal components. We then choose a subset of the principal components based on data-driven cutoffs, and estimate their strength as instruments with an adjusted F-statistic. Finally, we perform MR with these transformed exposures. This pipeline is demonstrated in a simulation study of highly correlated exposures and an applied example using summary data from a genome-wide association study of 97 highly correlated lipid metabolites. As a positive control, we tested the causal associations of the transformed exposures on CHD. Compared to the conventional inverse-variance weighted MVMR method and a weak-instrument robust MVMR method (MR GRAPPLE), sparse component analysis achieved a superior balance of sparsity and biologically insightful grouping of the lipid traits.
Le NN, Tran TQB, du Toit C, et al., 2023, Establishing plausibility of cardiovascular adverse effects of immunotherapies using Mendelian randomisation, Frontiers in Cardiovascular Medicine, Vol: 10, ISSN: 2297-055X
Immune checkpoint inhibitors (ICIs) and Janus kinase inhibitors (JAKis) have raised concerns over serious unexpected cardiovascular adverse events. The widespread pleiotropy in genome-wide association studies offers an opportunity to identify cardiovascular risks from in-development drugs to help inform appropriate trial design and pharmacovigilance strategies. This study uses the Mendelian randomization (MR) approach to study the causal effects of 9 cardiovascular risk factors on ischemic stroke risk both independently and by mediation, followed by an interrogation of the implicated expression quantitative trait loci (eQTLs) to determine if the enriched pathways can explain the adverse stroke events observed with ICI or JAKi treatment. Genetic predisposition to higher systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), waist-to-hip ratio (WHR), low-density lipoprotein cholesterol (LDL), triglycerides (TG), type 2 diabetes (T2DM), and smoking index were associated with higher ischemic stroke risk. The associations of genetically predicted BMI, WHR, and TG on the outcome were attenuated after adjusting for genetically predicted T2DM [BMI: 53.15% mediated, 95% CI 17.21%-89.10%; WHR: 42.92% (4.17%-81.67%); TG: 72.05% (10.63%-133.46%)]. JAKis, programmed cell death protein 1 and programmed death ligand 1 inhibitors were implicated in the pathways enriched by the genes related to the instruments for each of SBP, DBP, WHR, T2DM, and LDL. Overall, MR mediation analyses support the role of T2DM in mediating the effects of BMI, WHR, and TG on ischemic stroke risk and follow-up pathway enrichment analysis highlights the utility of this approach in the early identification of potential harm from drugs.
Au Yeung SL, Gill D, 2023, Standardizing the reporting of Mendelian randomization studies, BMC Medicine, Vol: 21, ISSN: 1741-7015
Cronjé HT, Karhunen V, Hovingh GK, et al., 2023, Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study, BMC Medicine, Vol: 21, ISSN: 1741-7015
Background:C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework.MethodsInstrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome.Results:Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer geneti
Cao L, Liu D, Karhunen V, et al., 2023, Circulating macrophage colony-stimulating factor levels and stroke: A Mendelian randomization study, JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, Vol: 32, ISSN: 1052-3057
Chen J, Yuan S, Fu T, et al., 2023, Gastrointestinal Consequences of Type 2 Diabetes Mellitus and Impaired Glycemic Homeostasis: A Mendelian Randomization Study, DIABETES CARE, Vol: 46, Pages: 828-835, ISSN: 0149-5992
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- Citations: 1
Kintu C, Soremekun O, Kamiza AB, et al., 2023, The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization study, EBIOMEDICINE, Vol: 90, ISSN: 2352-3964
Zhang Z, Wang M, Gill D, et al., 2023, Genetically Predicted Sleep Traits and Functional Outcome After Ischemic Stroke A Mendelian Randomization Study, NEUROLOGY, Vol: 100, Pages: E1159-E1165, ISSN: 0028-3878
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- Citations: 2
Yuan S, Wang L, Zhang H, et al., 2023, Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases, EBIOMEDICINE, Vol: 89, ISSN: 2352-3964
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- Citations: 1
Chalitsios CV, Georgiou A, Bouras E, et al., 2023, Investigating modifiable pathways in psoriasis: A Mendelian randomization study, JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, Vol: 88, Pages: 593-601, ISSN: 0190-9622
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- Citations: 1
Huang J, Gill D, Zuber V, et al., 2023, Circulatory proteins relate cardiovascular disease to cognitive performance: a Mendelian randomisation study, Frontiers in Genetics, Vol: 14, Pages: 1-11, ISSN: 1664-8021
Background and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment.Methods: We applied Mendelian randomisation (MR) and colocalization analysis to investigate the causal relationships of 90 CVD-related proteins measured by the Olink CVD I panel with cognitive traits. Genetic instruments for circulatory protein concentrations were obtained using a meta-analysis of genome-wide association studies (GWAS) from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis-pQTL (pQTL within ±500 kb from the coding gene); and 3) brain-specific cis-expression QTL (cis-eQTL) which accounts for coding gene expression based on GTEx8. Genetic associations of cognitive performance were obtained from GWAS for either: 1) general cognitive function constructed using Principal Component Analysis (N = 300,486); or, 2) g Factor constructed using genomic structural equation modelling (N = 11,263–331,679). Findings for candidate causal proteins were replicated using a separate protein GWAS in Icelanders (N = 35,559).Results: A higher concentration of genetically predicted circulatory myeloperoxidase (MPO) was nominally associated with better cognitive performance (p < 0.05) using different selection criteria for genetic instruments. Particularly, brain-specific cis-eQTL predicted MPO, which accounts for protein-coding gene expression in brain tissues, was associated with general cognitive function (βWald = 0.22, PWald = 2.4 × 10−4). The posterior probability for colocalization (PP.H4) of MPO pQTL with the g Factor was 0.577. Findings for MPO were replicated using the Icelandic GWAS. Although we did not find evidence for colocalization, we found that higher gene
Huang J, Su B, Karhunen V, et al., 2023, Inflammatory diseases, inflammatory biomarkers, and Alzheimer disease: an observational analysis and mendelian randomization, Neurology, Vol: 100, Pages: e568-e581, ISSN: 0028-3878
OBJECTIVES: Whether chronic autoimmune inflammatory diseases causally affect the risk of AD is controversial. We characterised the relationship between inflammatory diseases and the risk of AD and explore the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. METHODS: We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large scale genome-wide association study (GWAS) datasets, we performed two-sample Mendelian randomisation (MR) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. RESULTS: Cox regression models using CPRD data showed that overall incidence of AD was higher among patients with inflammatory bowel disease (IBD) (hazard ratio (HR)=1.17; 95%CI 1.15 to 1.19; P-value=2.1×10-4), other inflammatory polyarthropathies & systematic connective tissue disorders (OID) (HR=1.13; 95%CI 1.12 to 1.14; P-value=8.6×10-5), psoriasis (HR=1.13; 95%CI 1.10 to 1.16; P-value=2.6×10-4), rheumatoid arthritis (RA) (HR=1.08; 95%CI 1.06 to 1.11; P-value=4.0×10-4), and multiple sclerosis (MS) (HR=1.06; 95%CI 1.04 to 1.07; P-value=2.8×10-4) compared to the age (± 5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted (ORIVW)=1.23; 95%CI 1.06 to 1.42; PIVW=0.007), and lower risk of Crohn's disease (ORIVW=0.73; 95%CI -0.62, 0.86; PIVW=1.3×10
Burgess S, Mason AM, Grant AJ, et al., 2023, Using genetic association data to guide drug discovery and development: review of methods and applications, American Journal of Human Genetics, Vol: 110, Pages: 195-214, ISSN: 0002-9297
Evidence on the validity of drug targets from randomized trials is reliable but typically expensive and slow to obtain. In contrast, evidence from conventional observational epidemiological studies is less reliable because of the potential for bias from confounding and reverse causation. Mendelian randomization is a quasi-experimental approach analogous to a randomized trial that exploits naturally occurring randomization in the transmission of genetic variants. In Mendelian randomization, genetic variants that can be regarded as proxies for an intervention on the proposed drug target are leveraged as instrumental variables to investigate potential effects on biomarkers and disease outcomes in large-scale observational datasets. This approach can be implemented rapidly for a range of drug targets to provide evidence on their effects and thus inform on their priority for further investigation. In this review, we present statistical methods and their applications to showcase the diverse opportunities for applying Mendelian randomization in guiding clinical development efforts, thus enabling interventions to target the right mechanism in the right population group at the right time. These methods can inform investigators on the mechanisms underlying drug effects, their related biomarkers, implications for the timing of interventions, and the population subgroups that stand to gain the most benefit. Most methods can be implemented with publicly available data on summarized genetic associations with traits and diseases, meaning that the only major limitations to their usage are the availability of appropriately powered studies for the exposure and outcome and the existence of a suitable genetic proxy for the proposed intervention.
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