Rebecca Richmond

Numerous observational studies have identified nonlinear relationships between sleep duration and cardiometabolic risk, many of which highlight a U-shaped relationship with elevated risk among both short (< 7 hours) and long (> 8 hours) sleepers (1). Nonetheless, previous studies have typically relied on self-reported sleep duration and residual confounding remains problematic. In an attempt to overcome these issues and re-evaluate the relationship between sleep duration and visceral adiposity tissue, Yu et al. performed linear and nonlinear Mendelian randomization (MR) in the UK Biobank (n= 396 858), using 77 single nucleotide polymorphisms (SNPs) associated with sleep duration (2) as instrumental variables.The authors found evidence for nonlinearity between genetically predicted sleep duration and visceral adipose tissue (VAT), whereby short sleep duration (≤ 6 hours) increased VAT but with little …

DNA methylation (DNAm) is a developmentally dynamic epigenetic process, yet we still know little about how epigenetic effects on health outcomes vary over time; whether DNAm alterations during certain periods of development are more informative than others; and whether epigenetic timing effects differ by outcome. To address these questions, we applied longitudinal meta-regression to published meta-analyses from the PACE consortium that examine DNAm at multiple time points (prospectively at birth and cross-sectionally in childhood) in relation to the same child outcome (ADHD, general psychopathology, sleep, BMI, asthma). Our findings reveal three new insights: (i) across outcomes, effects sizes are larger when DNAm is measured in childhood compared to at birth; (ii) higher effect sizes do not necessarily translate into more significant findings, as associations also become noisier in childhood for most outcomes (i.e. showing larger standard errors); and (iii) DNAm signals are highly time-specific while showing pleiotropy across health outcomes

The detrimental health effects of smoking are well-known, but the impact of regular nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing daily use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). We used Genome-Wide Association Study (GWAS) summary statistics from Buchwald and colleagues, the GWAS and Sequencing Consortium of Alcohol and Nicotine, the International Lung Cancer Consortium, and UK Biobank. Increased nicotine metabolism increased the risk of COPD, lung cancer, and lung function in the univariable analysis. However, when accounting for smoking heaviness in the multivariable analysis, we found that increased nicotine metabolite ratio (indicative of decreased nicotine exposure per cigarette smoked) decreases heart rate (b = -0.30, 95% CI -0.50 to -0.10) and lung function (b = -33.33, 95% CI -41.76 to -24.90). There was no clear evidence of an effect on the remaining outcomes. The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential …

Background Observational evidence proposes a protective effect of having children and an early age at first birth on the development of breast cancer, however the causality of this association remains uncertain. In this study we assess whether these reproductive factors impact breast cancer risk independently of age at menarche, age at menopause, adiposity measures and other reproductive factors that have been identified as being causally related to or genetically correlated with the reproductive factors of interest. Methods We used genetic data from UK Biobank (273,238 women) for reproductive factors, age at menarche and menopause, and adiposity measures, and the Breast Cancer Association Consortium for risk of overall, estrogen receptor (ER) positive and negative breast cancer as well as breast cancer subtypes. We applied univariable and multivariable Mendelian randomization (MR) to estimate direct effects of ever parous status, ages at first birth and last birth, and number of births on breast cancer risk. Results We found limited evidence of an effect of age at first birth on overall or ER positive breast cancer risk in either the univariable or multivariable analyses. While the univariable analysis revealed an effect of later age at first birth decreasing ER negative breast cancer risk (Odds ratio (OR): 0.76, 95% confidence interval:0.61-0.95 per standard deviation (SD) increase in age at first birth), this effect attenuated with separate adjustment for age at menarche and menopause (e.g., OR 0.83, 0.62-1.06 per SD increase in age at first birth, adjusted for age at menarche). In addition, we found evidence for an effect of later age at first birth on …

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56%(95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.

DNA methylation changes in response to cigarette smoking are cell- and exposure-specific and indicate shared carcinogenic mechanisms with e-cigarette use — University of Bristol Skip to main navigation Skip to search Skip to main content University of Bristol Home University of Bristol Logo Help & Terms of Use Home Profiles Research units Research Outputs Projects Student theses Datasets Activities Prizes Facilities/Equipment Search by expertise, name or affiliation DNA methylation changes in response to cigarette smoking are cell- and exposure-specific and indicate shared carcinogenic mechanisms with e-cigarette use Chiara Herzog, Allison Jones, Iona Evans, Janhavi R. Raut, Michal Zikan, David Cibula, Andrew Wong, Hermann Brenner, Rebecca Richmond, Martin Widschwendter * * Corresponding author for this work Bristol Population Health Science Institute Bristol Medical School (PHS) Bristol …

Tobacco use is a major modifiable risk factor for adverse health outcomes, including cancer, and elicits profound epigenetic changes thought to be associated with long-term cancer risk. While electronic cigarettes (e-cigarettes) have been advocated as harm reduction alternatives to tobacco products, recent studies have revealed potential detrimental effects, highlighting the urgent need for further research into the molecular and health impacts of e-cigarettes. Here, we applied computational deconvolution methods to dissect the cell- and tissue-specific epigenetic effects of tobacco or e-cigarette use on DNA methylation (DNAme) in over 3,500 buccal/saliva, cervical, or blood samples, spanning epithelial and immune cells at directly and indirectly exposed sites. The 535 identified smoking-related DNAme loci (CpGs) clustered into four functional groups, including detoxification or growth signaling, based on cell …

BackgroundSmoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (<1 year), persistence of differential methylation from in utero smoking exposure, and effects of environmental tobacco smoke (ETS).MethodsWe meta-analysed data from up to 15,014 adults across 5 cohorts with DNA methylation measured in blood using Illumina's EPIC array for current smoking (2560 exposed), quit < 1 year (500 exposed), in utero (286 exposed), and ETS exposure (676 exposed). We also evaluated the interaction of current smoking with sex or diet (fibre, folate, and vitamin C).FindingsUsing false discovery rate (FDR < 0.05), 65,857 CpGs were differentially methylated in relation to current smoking, 4025 with recent quitting, 594 with in utero exposure, and 6 with ETS. Most current smoking CpGs attenuated within a year of quitting. CpGs …

BackgroundHigher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear.MethodsWe explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women.ResultsAll three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age …

PurposeTo investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.MethodsOur study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome.ResultsDuring a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence …

Background Diseases diagnosed in adulthood may have antecedents throughout - including prenatal - life. Gaining a better understanding of how exposures at different stages in the lifecourse influence health outcomes is key to elucidating the potential benefits of specific disease prevention strategies. However, confounding is highly likely in studies with earlier life or time-varying exposures. Mendelian randomisation (MR) is therefore increasingly used to estimate causal effects of exposures across the lifecourse on later life outcomes. Methods This systematic literature review aims to identify MR methods used to perform lifecourse investigations and review previous work that has utilised MR to elucidate the effects of factors acting at different stages of the lifecourse. We conducted a systematic search in PubMed, Embase, Medline and MedRXiv databases to comprehensively obtain lifecourse epidemiology studies that have employed MR. Results Thirteen methodological studies were identified. Four studies focused on the impact of time-varying exposures on the interpretation of "standard" MR techniques, five presented methods for analysing repeat measures of the same exposure, and four described novel methodological approaches to handling parental exposures in relation to offspring outcomes. A further 84 studies presented the results of an applied research question with relevance to lifecourse epidemiology. Over half of these estimated effects in a single generation and were largely confined to the exploration of questions regarding body composition. Of the one generational studies employed in this review, 59% estimated the effect of …

Insomnia and short/long sleep duration increase the risk of AMI, but their interaction with each other or with chronotype is not well known. We investigated the prospective joint associations of any two of these sleep traits on risk of AMI. We included 302 456 and 31 091 participants without past AMI episodes from UK Biobank (UKBB; 2006–10) and the Trøndelag Health Study (HUNT2; 1995–97), respectively. A total of 6 833 and 2 540 incident AMIs were identified during an average 11.7 and 21.0 years follow-up, in UKBB and HUNT2, respectively. Compared to those who reported normal sleep duration (7–8 h) without insomnia symptoms, the Cox proportional hazard ratios (HRs) for incident AMI in UKBB among participants who reported normal, short and long sleep duration with insomnia symptoms were 1.07 (95% CI 0.99, 1.15), 1.16 (95% CI 1.07, 1.25) and 1.40 (95% CI 1.21, 1.63), respectively. The …

Objective The aim of this study was to systematically evaluate the direction of any potential causal effect between sleep and adiposity traits. Methods Two‐sample Mendelian randomization was used to assess the association of genetically predicted sleep traits with adiposity and vice versa. Using data from UK Biobank and 23andMe, the sleep traits explored were morning preference (chronotype; N = 697,828), insomnia (N = 1,331,010), sleep duration (N = 446,118), napping (N = 452,633), and daytime sleepiness (N = 452,071). Using data from the Genetic Investigation of ANthropometric Traits (GIANT) and Early Growth Genetics (EGG) consortia, the adiposity traits explored were adult BMI, hip circumference (HC), waist circumference (WC), waist‐hip ratio (WHR; N = 322,154), and childhood BMI (N = 35,668). Results This study found evidence that insomnia symptoms increased mean WC, BMI, and WHR …

BackgroundFew studies have investigated the joint effects of sleep traits on the risk of acute myocardial infarction (AMI). No previous study has used factorial Mendelian randomization (MR) which may reduce confounding, reverse causation, and measurement error. Thus, it is prudent to study joint effects using robust methods to propose sleep-targeted interventions which lower the risk of AMI.MethodsThe causal interplay between combinations of two sleep traits (including insomnia symptoms, sleep duration, or chronotype) on the risk of AMI was investigated using factorial MR. Genetic risk scores for each sleep trait were dichotomized at their median in UK Biobank (UKBB) and the second survey of the Trøndelag Health Study (HUNT2). A combination of two sleep traits constituting 4 groups were analyzed to estimate the risk of AMI in each group using a 2×2 factorial MR design.ResultsIn UKBB, participants with …

Abstract A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption, and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes (T2D) and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted [IVW] method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data were taken from the largest available GWAS of 6034 oral and oropharyngeal cases, with 6585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (BMI; OR IVW= 0.89, 95% CI 0.72–1.09, p= 0.26 per 1 standard deviation in BMI [4.81 kg/m2]) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including T2D and hypertension. Small effects cannot be excluded given the lack of power to detect them in currently available GWAS.

Background Epigenetic alterations may provide valuable insights into gene–environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohn’s disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD …

BackgroundFurther investigation is warranted to understand the potential role of nicotine on sleep, considering the negative health effects of both sleep disturbances and smoking and the popularity of alternative nicotine product use to stop smoking. This study aimed to examine the direct effect of nicotine on sleep behaviours while accounting for non-nicotine constituents of tobacco smoke.MethodsWe conducted a two-sample multivariable Mendelian Randomisation study using genetic proxies for nicotine metabolite ratio (NMR) (N SNP = 6) and cigarettes per day (CPD) (N SNP = 53) and six sleep outcomes, stratified by smoking status in ∼500,000 individuals in the UK Biobank.ResultsWe found evidence that increased NMR decreases the likelihood of being an evening person when accounting for CPD in current (β= -0.04, 95%CI= -0.06, -0.02, P= < 0.001) and ever smokers (β= -0.03 95%CI= -0.04, -0.01, P …

Introduction The overall incidence of head and neck cancer (HNC) continues to rise, despite a decline in smoking rates, particularly within developed countries. Obesity and related metabolic traits have been attributed to a growth in cancer rate, so further exploration of these risk factors is warranted in HNC. A comprehensive systematic review and meta-analysis was conducted in order to obtain the most precise observational estimates between metabolic trait exposures and risk of HNC. Methods A search strategy was developed with an information and content specialists. Multiple databases including Cochrane Library, OVID SP versions of Medline, EMBASE, pre-prints and the grey literature were searched. The primary outcome for included studies was incident HNC and exposures included obesity defined by body mass index (BMI), type 2 diabetes, dyslipidaemia, and hypertension, using pre-specified definitions. A combined risk effect across studies was calculated using both fixed and random-effects meta-analysis. Heterogeneity was assessed between studies using the Cochrans Q and I2 statistical tests. The ROBINS-E preliminary tool was used to assess the bias in each included result. Results The search generated 7,316 abstracts, of these 197 full text articles were assessed for eligibility and 36 were included for full qualitative and quantitative synthesis. In the analysis of 5 studies investigating the association between obesity and incidence of HNC, there was an overall RR of 1.06 (95%CI (0.76, 1.49), P heterogeneity <0.024, I2= 73.2%) using a random-effects model. 6 studies reported on the association between type 2 diabetes and …

ObjectivesTo identify whether Mendelian randomisation (MR) studies are appropriately conducted and reported in enough detail for other researchers to accurately replicate and interpret them.DesignCross-sectional meta-epidemiological study.Data sourcesWeb of Science, EMBASE, PubMed and PsycINFO were searched on 15 July 2022 for literature.Eligibility criteriaFull research articles that conducted an MR analysis exclusively using individual-level UK Biobank data to obtain a causal estimate of the exposure–outcome relationship (for no more than ten exposures or outcomes).Methods and analysisData were extracted using a 25-item checklist relating to reporting and methodological quality (based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)-MR reporting guidelines and the guidelines for performing MR investigations). Article characteristics, such as 2021 Journal …

BackgroundFew studies have investigated associations between adiposity and reproductive factors using causal methods, both of which have a number of consequences on women’s health. Here we assess whether adiposity at different points in the lifecourse affects reproductive factors differently and independently, and the plausibility of the impact of reproductive factors on adiposity.MethodsWe used genetic data from UK Biobank (273,238 women) and other consortia (EGG, GIANT, ReproGen and SSGAC) for eight reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners, and two adiposity traits: childhood and adulthood body size. We applied multivariable Mendelian randomization to account for genetic correlation and to estimate the causal effects of childhood and …