Investigating the causal effects of childhood and adulthood adiposity on later life mental health outcome: a Mendelian randomization study.

Background: Obesity particularly during childhood is considered a global public health crisis and has been linked with later life health consequences including mental health. However, there is lack of causal understanding if childhood body size has a direct effect on mental health or has an indirect effect after accounting for adulthood body size.

Methods: Two-sample Mendelian randomization (MR) was performed to estimate the total effect and direct effect (accounting for adulthood body size) of childhood body size on anxiety and depression.

Evaluating causal associations of chronotype with pregnancy and perinatal outcomes and its interactions with insomnia and sleep duration: a mendelian randomization study.

Background: Observational studies suggested chronotype was associated with pregnancy and perinatal outcomes. Whether these associations are causal is unclear. Our aims are to use Mendelian randomization (MR) to explore (1) associations of evening preference with stillbirth, miscarriage, gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth and offspring birthweight; and (2) differences in associations of insomnia and sleep duration with those outcomes between chronotype preferences.

Estimating and visualising multivariable Mendelian randomization analyses within a radial framework.

Background: Mendelian randomization (MR) is a statistical approach using genetic variants as instrumental variables to estimate causal effects of a single exposure on an outcome. Multivariable MR (MVMR) extends this to estimate the direct effect of multiple exposures simulatiously. MR and MVMR can be biased by the presence of pleiotropic genetic variants in the set used as instrumental variables, violating one of the core IV assumptions.

Reading and conducting instrumental variable studies: guide, glossary, and checklist.

Instrumental variable analysis uses naturally occurring variation to estimate the causal effects of treatments, interventions, and risk factors on outcomes in the population from observational data. Under specific assumptions, instrumental variable methods can provide unbiased estimates of causal effects. This article explains these assumptions and the information and tests typically reported in instrumental variable studies, which can assess the credibility of the findings of instrumental variable studies.

Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study.

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls.

Exploring pleiotropy in Mendelian randomisation analyses: What are genetic variants associated with 'cigarette smoking initiation' really capturing?

Genetic variants used as instruments for exposures in Mendelian randomisation (MR) analyses may have horizontal pleiotropic effects (i.e., influence outcomes via pathways other than through the exposure), which can undermine the validity of results.

Serum vitamin D, blood pressure and hypertension risk in the HUNT study using observational and Mendelian randomization approaches.

Limited studies have triangulated the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and systolic blood pressure (SBP), diastolic blood pressure (DBP) or hypertension risk utilizing both observational and Mendelian randomization (MR) approaches. We employed data from the Norwegian Trøndelag Health Study (HUNT) to conduct cross-sectional (n = 5854) and prospective (n = 3592) analyses, as well as one-sample MR (n = 86,324). We also used largest publicly available data for two-sample MR.

Mammographic density mediates the protective effect of early-life body size on breast cancer risk.

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.

Estimating the health impact of nicotine exposure by dissecting the effects of nicotine versus non-nicotine constituents of tobacco smoke: A multivariable Mendelian randomisation study.

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]).

Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: A systematic literature review.

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 disease prevention strategies. Mendelian randomisation (MR) is increasingly used to estimate causal effects of exposures across the lifecourse on later life outcomes.

Chronic inflammation does not mediate the effect of adiposity on grip strength: results from a multivariable Mendelian randomization study.

The relationship between adiposity and grip strength (GS) is complex. We investigated whether one pathway through which adiposity affects GS was via chronic inflammation. 367,583 UK Biobank participants had body mass index (BMI), waist-hip-ratio (WHR), C-reactive protein (CRP) and GS data.

The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study.

Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR). We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects.

Causal factors in primary open angle glaucoma: a phenome-wide Mendelian randomisation study.

Primary open angle glaucoma (POAG) is a chronic, adult-onset optic neuropathy associated with characteristic optic disc and/or visual field changes. With a view to identifying modifiable risk factors for this common neurodegenerative condition, we performed a 'phenome-wide' univariable Mendelian randomisation (MR) study that involved analysing the relationship between 9661 traits and POAG. Utilised analytical approaches included weighted mode based estimation, the weighted median method, the MR Egger method and the inverse variance weighted (IVW) approach.

Evaluating causal associations of chronotype with pregnancy and perinatal outcomes and its interactions with insomnia and sleep duration: a Mendelian randomization study.

Importance: Observational studies suggest that chronotype is associated with pregnancy and perinatal outcomes. Whether these associations are causal is unclear.

Objective: To explore associations of a lifetime genetic predisposition to an evening preference chronotype with pregnancy and perinatal outcomes, and explore differences in associations of insomnia and sleep duration with those outcomes between chronotype.

Investigating causality in the association between DNA methylation and type 2 diabetes using bidirectional two-sample Mendelian randomisation.

Aims/hypothesis: Several studies have identified associations between type 2 diabetes and DNA methylation (DNAm). However, the causal role of these associations remains unclear. This study aimed to provide evidence for a causal relationship between DNAm and type 2 diabetes.

Glycoprotein acetyls and depression: Testing for directionality and potential causality using longitudinal data and Mendelian randomization analyses.

Background: Inflammation is associated with depression, but causality remains unclear. We investigated potential causality and direction of effect between inflammation and depression.

Methods: Using data from the ALSPAC birth cohort (n = 4021; 42.

A genome-wide association study of childhood adiposity and blood lipids.

The rising prevalence of childhood obesity and dyslipidaemia is a major public health concern due to its association with morbidity and mortality in later life. Previous studies have found that genetic variants inherited at birth can begin to exert their effects on cardiometabolic traits during the early stages of the lifecourse. In this study, we have conducted genome-wide association studies (GWAS) for eight measures of adiposity and lipids in a cohort of young individuals (mean age 9.

Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study.

Background: Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood.

Methods: We used large-scale metabolomics data in a two-sample reverse Mendelian randomization (MR) framework to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites in the UK Biobank (N = 118,466). We examined the potential for medication use to distort effect estimates by conducting age-stratified metabolite analyses.

Intergenerational effects of parental educational attainment on parenting and childhood educational outcomes: Evidence from MoBa using within-family Mendelian randomization.

The intergenerational transmission of educational attainment from parents to their children is one of the most important and studied relationships in social science. Longitudinal studies have found strong associations between parents' and their children's educational outcomes, which could be due to the effects of parents. Here we provide new evidence about whether parents' educational attainment affects their parenting behaviours and children's early educational outcomes using within-family Mendelian randomization and data from 40,879 genotyped parent-child trios from the Norwegian Mother, Father and Child Cohort (MoBa) study.

Phenome-wide Mendelian randomisation analysis identifies causal factors for age-related macular degeneration.

Background: Age-related macular degeneration (AMD) is a leading cause of blindness in the industrialised world and is projected to affect >280 million people worldwide by 2040. Aiming to identify causal factors and potential therapeutic targets for this common condition, we designed and undertook a phenome-wide Mendelian randomisation (MR) study.

Methods: We evaluated the effect of 4591 exposure traits on early AMD using univariable MR.

Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: A within-family Mendelian randomization study.

Background: Higher BMI in childhood is associated with emotional and behavioural problems, but these associations may not be causal. Results of previous genetic studies imply causal effects but may reflect influence of demography and the family environment.

Methods: This study used data on 40,949 8-year-old children and their parents from the Norwegian Mother, Father and Child Cohort Study (MoBa) and Medical Birth Registry of Norway (MBRN).