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.

Small-cohort GWAS discovery with AI over massive functional genomics knowledge graph.

Genome-wide association studies (GWASs) have identified tens of thousands of disease associated variants and provided critical insights into developing effective treatments. However, limited sample sizes have hindered the discovery of variants for uncommon and rare diseases. Here, we introduce KGWAS, a novel geometric deep learning method that leverages a massive functional knowledge graph across variants and genes to improve detection power in small-cohort GWASs significantly.

The role of body image dissatisfaction in the relationship between body size and disordered eating and self-harm: complimentary Mendelian randomization and mediation analyses.

Disordered eating and self-harm commonly co-occur in young people suggesting potential for shared underlying causes. Body image dissatisfaction (BID) has been recognised as a psychological correlate of body size, associated with both disordered eating and self-harm. However, the investigation into etiological pathways early in the lifecourse to provide detail on how body size and BID may foster disordered eating and self-harm remains largely unexplored.

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.

Childhood adiposity underlies numerous adult brain traits commonly attributed to midlife obesity.

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study investigated whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity.

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.

Characterizing the Causal Pathway From Childhood Adiposity to Right Heart Physiology and Pulmonary Circulation Using Lifecourse Mendelian Randomization.

Background: Observational epidemiological studies have reported an association between childhood adiposity and altered cardiac morphology and function in later life. However, whether this is due to a direct consequence of being overweight during childhood has been difficult to establish, particularly as accounting for other measures of body composition throughout the lifecourse can be exceptionally challenging.

Methods And Results: In this study, we used human genetics to investigate this using a causal inference technique known as lifecourse Mendelian randomization.

Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes.

Background: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown.

Profiling the genome and proteome of metabolic dysfunction-associated steatotic liver disease identifies potential therapeutic targets.

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 25% of the population and currently has no effective treatments. Plasma proteins with causal evidence may represent promising drug targets. We aimed to identify plasma proteins in the causal pathway of MASLD and explore their interaction with obesity.

A lifecourse Mendelian randomization study uncovers age-dependent effects of adiposity on asthma risk.

Evaluating the long-term consequences of childhood lifestyle factors on asthma risk can be exceptionally challenging in epidemiology given that cases are typically diagnosed at various timepoints throughout the lifecourse. In this study, we used human genetic data to evaluate the effects of childhood and adulthood adiposity on risk of pediatric (n = 13,962 cases) and adult-onset asthma (n = 26,582 cases) with a common set of controls (n = 300,671) using a technique known as lifecourse Mendelian randomization. We found that childhood adiposity directly increases risk of pediatric asthma (OR = 1.

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.

Time-varying and tissue-dependent effects of adiposity on leptin levels: A Mendelian randomization study.

Background: Findings from Mendelian randomization (MR) studies are conventionally interpreted as lifelong effects, which typically do not provide insight into the molecular mechanisms underlying the effect of an exposure on an outcome. In this study, we apply two recently developed MR approaches (known as 'lifecourse' and 'tissue-partitioned' MR) to investigate lifestage-specific effects and tissues of action in the relationship between adiposity and circulating leptin levels.

Methods: Genetic instruments for childhood and adult adiposity were incorporated into a multivariable MR (MVMR) framework to estimate lifestage-specific effects on leptin levels measured during early life (mean age: 10 y) in the Avon Longitudinal Study of Parents and Children and in adulthood (mean age: 55 y) using summary-level data from the deCODE Health study.

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.

Educational inequality in multimorbidity: causality and causal pathways. A mendelian randomisation study in UK Biobank.

Background: Multimorbidity, typically defined as having two or more long-term health conditions, is associated with reduced wellbeing and life expectancy. Understanding the determinants of multimorbidity, including whether they are causal, may help with the design and prioritisation of prevention interventions. This study seeks to assess the causality of education, BMI, smoking and alcohol as determinants of multimorbidity, and the degree to which BMI, smoking and alcohol mediate differences in multimorbidity by level of education.

Genetic evidence that high BMI in childhood has a protective effect on intermediate diabetes traits, including measures of insulin sensitivity and secretion, after accounting for BMI in adulthood.

Aims/hypothesis: Determining how high BMI at different time points influences the risk of developing type 2 diabetes and affects insulin secretion and insulin sensitivity is critical.

Methods: By estimating childhood BMI in 441,761 individuals in the UK Biobank, we identified which genetic variants had larger effects on adulthood BMI than on childhood BMI, and vice versa. All genome-wide significant genetic variants were then used to separate the independent genetic effects of high childhood BMI from those of high adulthood BMI on the risk of type 2 diabetes and insulin-related phenotypes using Mendelian randomisation.

Leveraging family history data to disentangle time-varying effects on disease risk using lifecourse mendelian randomization.

Lifecourse Mendelian randomization is a causal inference technique which harnesses genetic variants with time-varying effects to develop insight into the influence of age-dependent lifestyle factors on disease risk. Here, we apply this approach to evaluate whether childhood body size has a direct consequence on 8 major disease endpoints by analysing parental history data from the UK Biobank study.Our findings suggest that, whilst childhood body size increases later risk of outcomes such as heart disease (odds ratio (OR) = 1.

Age-specific effects of weight-based body size on fracture risk in later life: a lifecourse Mendelian randomisation study.

Musculoskeletal conditions, including fractures, can have severe and long-lasting consequences. Higher body mass index in adulthood is widely acknowledged to be protective for most fracture sites. However, sources of bias induced by confounding factors may have distorted previous findings.

Genetic variation and elevated liver enzymes during childhood, adolescence and early adulthood.

Background: Genetic factors influence the risk of fatty liver disease (FLD) in adults. The aim of this study was to test if, and when, genetic risk factors known to affect FLD in adults begin to exert their deleterious effects during childhood, adolescence and early adulthood.

Methods: We included up to 4018 British children and adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.

Life course effects of genetic susceptibility to higher body size on body fat and lean mass: prospective cohort study.

Background/objectives: Different genetic variants are associated with larger body size in childhood vs adulthood. Whether and when these variants predominantly influence adiposity are unknown. We examined how genetic variants influence total body fat and total lean mass trajectories.

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.

Childhood adiposity and novel subtypes of adult-onset diabetes: a Mendelian randomisation and genome-wide genetic correlation study.

Aims/hypothesis: We investigated whether the impacts of childhood adiposity on adult-onset diabetes differ across proposed diabetes subtypes using a Mendelian randomisation (MR) design.

Methods: We performed MR analysis using data from European genome-wide association studies of childhood adiposity, latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD).

Results: Higher levels of childhood adiposity had positive genetically predicted effects on LADA (OR 1.