George Davey Smith

George Davey Smith
University of Bristol | UB · School of Social and Community Medicine

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1,507
Publications
226,458
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Introduction
Skills and Expertise

Publications

Publications (1,507)
Article
Full-text available
Romososumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)‐related events in a pivotal phase III trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yie...
Article
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Objectives To examine whether acetabular dysplasia (AD), cam and/or pincer morphology are associated with radiographic hip osteoarthritis (rHOA) and hip pain in UK Biobank (UKB) and, if so, what distribution of osteophytes is observed. Design Participants from UKB with a left hip dual-energy x-ray absorptiometry (DXA) scan had alpha angle (AA), la...
Article
Full-text available
Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibit...
Article
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 e...
Article
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Background Obesity has tripled worldwide since 1975 as environments are becoming more obesogenic. Our study investigates how changes in population weight and obesity over time are associated with genetic predisposition in the context of an obesogenic environment over 6 decades and examines the robustness of the findings using sibling design. Metho...
Article
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From a life-course perspective, genetic and environmental factors driving childhood obesity may have a lasting influence on health later in life. However, how obesity trajectories vary throughout the life-course remains unknown. Recently, Richardson et al. created powerful early life and adult gene scores for BMI in a comprehensive attempt to separ...
Preprint
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Greater blood pressure variability (BP) and reduced night-time BP dipping are associated with cardiovascular disease independently of mean BP in adults. This study examines whether these associations are apparent in adolescents. A cross-sectional analysis was undertaken in 587 UK adolescents. We examined associations between measures of blood press...
Article
Background Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. Purpose We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual's genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are exp...
Article
Background We aimed to quantify the role of the plasma metabolic profile in explaining the effect of adiposity on cardiac structure. Methods and Results Body mass index (BMI) was measured at age 11 in the Avon Longitudinal Study of Parents and Children. Left ventricular mass indexed to height 2.7 (LVMI) was assessed by echocardiography at age 17....
Preprint
The genes that encode the targets of most therapies do not have rare variants with large-effect or common variants with moderate effects on the biomarker reflecting the pharmacologic action of the corresponding therapy. Therefore, providing genetic target validation for most therapies is challenging. Novel methods are being developed to combine mul...
Article
Full-text available
Importance Preclinical and epidemiological studies indicate a potential chemopreventive role of statins in epithelial ovarian cancer risk. Objective To evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ie, genetic variants related to lower function of HMG-CoA reductase, target...
Conference Paper
Background Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of physical health problems, including cardiometabolic, neurological and immunological conditions. Determining whether ADHD plays a causal role in these associations is of great importance not only for early treatment and prevention but also because comorbid...
Conference Paper
Background Studies have demonstrated causal effects of educational attainment on cardiovascular disease (CVD). We aimed to investigate the role of body mass index (BMI), systolic blood pressure (SBP) and smoking in explaining the effect of education on risk of CVD outcomes triangulating across multivariable regression analysis of observational data...
Article
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Background: The link between adiposity, metabolic abnormalities, and arterial disease progression in children and adolescents remains poorly defined. We aimed to assess whether persistent high adiposity levels are associated with increased arterial stiffness in adolescence and any mediation effects by common metabolic risk factors. Methods: We i...
Article
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Participants in epidemiologic and genetic studies are rarely true random samples of the populations they are intended to represent, and both known and unknown factors can influence participation in a study (known as selection into a study). The circumstances in which selection causes bias in an instrumental variable (IV) analysis are not widely und...
Article
Background Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear. Objectives The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits...
Article
Background: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). Methods: T...
Conference Paper
Full-text available
Background Shift work is a feature of many occupations and has been associated with a range of adverse health outcomes, including obesity, diabetes, depression and cancer. The main proposed mechanism linking them is a disruption in circadian rhythms, particularly among night shift workers. DNA methylation may serve as a biomarker for circadian disr...
Article
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Aims: To determine the impact of smoking and alcohol exposure during adolescence on arterial stiffness at 17 years. Methods and results: Smoking and alcohol use were assessed by questionnaires at 13, 15, and 17 years in 1266 participants (425 males and 841 females) from the ALSPAC study. Smoking status (smokers and non-smoker) and intensity (‘high’...
Article
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BACKGROUND: Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages—nor with detailed cardiovascular phenotyping. Recall-by-Genotype (RbG) is an approach that enables the collection of precise phenotypic measures in smaller studies, w...
Article
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2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Several studies have shown that diabetes confers a higher relative risk of vascular mortality among women than among men, but whether this increased relative risk in women exists across age groups and within defined levels of other...
Article
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Motivation: DNA methylation datasets are growing ever larger both in sample size and genome coverage. Novel computational solutions are required to efficiently handle these data. Results: We have developed meffil, an R package designed for efficient quality control, normalization and epigenome-wide association studies of large samples of Illumin...
Article
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In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 lg/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian randomization analysis uses genetic variants to proxy modifiable risk factor...
Article
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BACKGROUND: CETP inhibition reduces vascular event rates but confusion surrounds its low-density lipoprotein (LDL)-cholesterol effects. We sought to clarify associations of genetic inhibition of CETP on detailed lipoproteins. METHODS AND RESULTS: We used variants associated with CETP (rs247617) and HMGCR (rs12916) expression in 62,400 Europeans wit...
Preprint
Full-text available
DNA methylation changes in peripheral blood have been identified in relation to lung cancer risk. However, the causal nature of these associations remains to be fully elucidated. Meta-analysis of four epigenome-wide association studies (918 cases, 918 controls) revealed differential methylation at 16 CpG sites (FDR < 0.05) in relation to lung cance...
Article
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The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to enviro...
Article
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Hair cortisol concentration (HCC) is a promising measure of long-Term hypothalamus-pituitary-Adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables sh...
Preprint
Full-text available
Insulin may serve as a key causal agent which regulates fat accumulation in the body. Here we assessed the causal relationship between fasting insulin and adiposity using publicly-available results from two large-scale genome-wide association studies for body mass index and fasting insulin levels in a two-sample, bidirectional Mendelian Randomized...
Article
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Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic ins...
Article
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The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ~370,000 women, we identify 389 independent signals (P < 5 × 10$^{−8}$) for age at menarche, a milestone in female pubertal development. In Icelandic data, these sign...
Article
Full-text available
Several studies have investigated the relationship between genetic variation and DNA methylation with respect to type 2 diabetes but it is unknown if DNA methylation is a mediator in the disease pathway or if it is altered in response to disease state. This study uses genotypic information as a causal anchor to help decipher the likely role of DNA...
Article
Obtaining reliable evidence regarding factors that cause disease or influence disease progression is clearly central to progress in science. There have been many high-profile failures in this regard, which range from health-related behaviors (eg, dietary components that observational epidemiology strongly suggested protected against chronic disease...
Article
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Mendelian randomization (MR), the use of genetic variants as instrumental variables (IVs) to test causal effects, is increasingly used in aetiological epidemiology. Few of the methodological developments in MR have considered the specific situation of using genetic IVs to test the causal effect of exposures in pregnant women on postnatal offspring...
Article
Background and objective: There is a well-documented association between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD). The degree to which this reflects causal intrauterine effects or is due to unmeasured confounding is not clear. We sought to compare the association between maternal smoking durin...
Article
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Background It has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to...
Data
Forest plot of association between maternal BMI and offspring BMI using multivariable linear regression in ALSPAC and Generation R. (DOCX)
Data
Multivariable and instrument variable meta-analysis to assess the association between maternal BMI and offspring BMI in ALSPAC and Generation R, additionally adjusted for paternal education in the IV analysis. (DOCX)
Data
Augmented partial residual plots to evaluate departures from linearity in observational and IV models from the Generation R main analysis. (DOCX)
Data
Association between transmitted and non-transmitted maternal haplotype scores and offspring BMI at age 7 in ALSPAC (Total n = 3,720). (DOCX)
Data
Confounder-adjusted multivariable associations of maternal pregnancy BMI with offspring BMI and FMI from ages 7 to 18 in ALSPAC (Discovery sample). (DOCX)
Data
Details of the BMI SNPs obtained from genotyping and imputation. (DOCX)
Data
Associations between maternal BMI and maternal BMI allele score and possible confounding factors in ALSPAC. (DOCX)
Data
Associations between maternal BMI and offspring FMI from ages 10 to 18 using multivariable and IV methods with a 32-SNP allele score in the ALSPAC (Discovery) cohort. (DOCX)
Data
Association between maternal BMI and offspring FMI from ages 7 to 18 using multivariable and IV methods with a 97-SNP allele score. (DOCX)
Data
Forest plot of association between maternal BMI allele score and offspring BMI using multivariable linear regression in ALSPAC and Generation R. (DOCX)
Data
Scatterplot of maternal genetic associations with offspring BMI (adjusted for offspring genetic variants) against maternal genetic associations with maternal BMI, with causal estimates of maternal BMI on offspring BMI estimated by MR-Egger (solid line) and IVW (dashed line) methods. (DOCX)
Data
Augmented partial residual plots to evaluate departures from linearity in observational and IV models from the ALSPAC main analysis. (DOCX)
Data
F-statistics for first-stage regression of IV analyses in ALSPAC and Generation R. (DOCX)
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Associations between maternal BMI and maternal BMI allele score and possible confounding factors in Generation R. (DOCX)
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Supplementary methods for investigating potential collider bias and the analysis plan. (DOCX)
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Schematic diagram showing relationships for the MR analysis and how “collider bias” might occur when adjusting for offspring genotype. (DOCX)
Data
Multivariable and instrument variable meta-analysis to assess the association between maternal BMI and offspring BMI in ALSPAC and Generation R, restricted to European ancestry. (DOCX)
Data
Descriptive characteristics of included participants in ALSPAC at each age. (DOCX)
Data
Characteristics of maternal BMI allele score and association with maternal BMI. (DOCX)
Data
Associations between maternal BMI and offspring BMI from ages 7 to 18 using multivariable and IV methods with a 32-SNP allele score in ALSPAC (Discovery) cohort. (DOCX)
Data
Association between maternal BMI and offspring BMI from ages 7 to 18 using multivariable and IV methods with a 97-SNP allele score. (DOCX)