George Davey Smith

Serum Vitamin D Levels do not Affect Susceptibility to EBV Infection. A Mendelian Randomization Study.

Introduction: Epstein-Barr virus (EBV) infection and low serum 25-hydroxyvitamin D (25OHD) levels are strongly associated with multiple sclerosis (MS). We investigated whether genetically proxied serum vitamin D levels are causally linked to EBV infection, assessed by serology and detectable EBV DNA, using Mendelian randomisation (MR). Methods: We conducted two-sample cis-MR using genetic instruments associated with serum 25OHD concentrations, restricted to variants near genes implicated in vitamin D metabolism. Outcomes included EBV seropositivity, antibody responses to four EBV antigens, detectable EBV DNA in blood and saliva, and MS case status as a positive control. Results: Genetically proxied vitamin D levels had no clear effect on EBV seropositivity (odds ratio per standard deviation (SD) increase in rank-based inverse-normal transformation (RINT) 25OHD: 1.76, 95% confidence interval [CI] 0.83-3.73) or antibody responses to EBV antigens. No significant associations were observed with detectable EBV DNA in blood (beta 0.02, 95% CI −0.004 to 0.04) or saliva (beta 0.02, 95% CI −0.23 to 0.26). In contrast, genetically proxied vitamin D levels were associated with reduced MS risk (odds ratio per SD increase in RINT 25OHD 0.67, 95% CI 0.54-0.84). Discussion: We found no clear evidence that genetically proxied vitamin D levels causally influence EBV serological responses or detectable EBV DNA in blood or saliva. The protective association with MS supports previous genetic evidence. These findings suggest that vitamin D and EBV may influence MS risk through distinct pathways, although effects specific to early-life vitamin D exposure remain possible.

A genetically proxied 5-mmHg overall systolic BP reduction was associated with an 8% decrease in the risk of NAFLD (OR 0.92; 95% CI, 0.90-0.94), while genetic proxies for RAS inhibition were associated with a 27% reduction (OR 0.73; 95% CI, 0.62-0.85).

Genetically predicted reductions in systolic blood pressure, particularly through renin-angiotensin system inhibition, are associated with a significantly lower risk of metabolic associated fatty liver disease.

JUN 1991MarmotThe Lancet

Health inequalities among British civil servants: the Whitehall II study

The Whitehall study of British civil servants begun in 1967, showed a steep inverse association between social class, as assessed by grade of employment, and mortality from a wide range of diseases. Between 1985 and 1988 we investigated the degree and causes of the social gradient in morbidity in a new cohort of 10,314 civil servants (6900 men, 3414 women) aged 35-55 (the Whitehall II study). Participants were asked to answer a self-administered questionnaire and attend a screening examination. In the 20 years separating the two studies there has been no diminution in social class difference in morbidity: we found an inverse association between employment grade and prevalence of angina, electrocardiogram evidence of ischaemia, and symptoms of chronic bronchitis. Self-perceived health status and symptoms were worse in subjects in lower status jobs. There were clear employment-grade differences in health-risk behaviours including smoking, diet, and exercise, in economic circumstances, in possible effects of early-life environment as reflected by height, in social circumstances at work (eg, monotonous work characterised by low control and low satisfaction), and in social supports. Healthy behaviours should be encouraged across the whole of society; more attention should be paid to the social environments, job design, and the consequences of income inequality.

Dietary pattern and epigenetic aging: a longitudinal twin study

Longitudinal twin study reveals diet-linked slowdowns in epigenetic aging attenuate within twin pairs, indicating familial factors drive apparent benefits.

Evaluating the consequences of childhood adiposity on the human plasma proteome at four timepoints across the lifecourse

Mendelian randomization study reveals proteomic shifts from childhood adiposity in cohorts across life stages, highlighting persistent risks for childhood asthma and adult breast cancer.

Robust inference and correlates from genetic associations with personality

Genome-wide meta-analysis reveals robust genetic architecture for Big Five traits across diverse cohorts, indicating direct genetic influences minimally confounded by shared family environments.

Genetic and behavioural architecture of childhood eating behaviour and links to obesity risk

Background/Objectives Childhood appetitive traits are heritable behavioural phenotypes hypothesized to link genetic susceptibility to obesity risk. Yet their genetic architecture and role in mediating polygenic adiposity risk remain poorly understood. Methods We conducted the largest survey of childhood eating behaviour to date, allowing us to perform genome-wide association studies of six appetitive domains derived from 18 items of the parent-reported Children’s Eating Behaviour Questionnaire in up to 31,018 eight-year-old children from the Norwegian Mother, Father and Child Cohort Study (MoBa). A trio-based design enabled decomposition of direct and indirect genetic effects on appetite and BMI. Results We identified ten independent genome-wide significant loci for childhood eating behaviour, primarily across Food Responsiveness , Satiety Responsiveness , and Food Fussiness , eight of which lie at established childhood or adult BMI loci. Food Responsiveness and Satiety Responsiveness showed both phenotypic and genetic correlations with BMI trajectories from early childhood through adolescence. Statistical mediation analyses indicated that 22.1% and 10.4% of the aggregated genetic association with BMI at age 8 could be decomposed through these traits, respectively. Locus-specific patterns further suggested mechanistic pathways, with the FTO locus acting predominantly via Food Responsiveness , and the ADCY3 locus via Satiety Responsiveness . Trio analyses demonstrated that both BMI and eating behaviour associations were predominantly explained by children’s inherited alleles, with minimal contribution from indirect effect from parental adiposity, although parental genetic liability influenced reporting of Satiety Responsiveness . Conclusions Childhood appetitive traits capture a substantial proportion of genetic susceptibility to adiposity through distinct eating behaviour pathways (under standard mediation assumptions). These effects are primarily driven by the child’s own genotype rather than indirect parental influences, positioning appetite as a plausible, biologically grounded target for early obesity prevention.

Effects of maternal and paternal smoking on offspring cardiometabolic risk factors in adulthood: a multi-method intergenerational Mendelian randomization study

Evaluating bias in target trial emulation for heart failure across statistical and deep learning methods

Can we identify people with Alzheimer’s disease from examination of the eye? A bidirectional Mendelian randomization (MR) study

Identifies neurovascular changes in the eye due to Alzheimer’s disease, suggesting potential for early detection.

Correction: A protocol for using human genetic data to identify circulating protein level changes that are the causal consequence of cancer processes

Correction implements a protocol to analyze genetic data and changes in protein levels linked to cancer processes.

Parental body mass index and offspring childhood body size and eating behaviour: A structural equation modelling analysis in the Norwegian Mother, Father and Child Cohort Study

MAY 29SmithEpidemiology

The Illusion of the “Self-correcting” Nature of Science

Elevated plasma glycerol is linked to ~31% higher all-cause mortality.

Higher triglyceride metabolism, measured by plasma glycerol and β-hydroxybutyrate, is associated with increased all-cause, cardiovascular, and cancer mortality independent of plasma triglycerides and body mass index.

Association between childhood ADHD problems and premature mortality: identifying modifiable cardiovascular mechanisms in a UK population cohort

Background Individuals with attention deficit hyperactivity disorder (ADHD) are at increased risk of premature mortality, but the mechanisms that underlie this association after young adulthood are unknown. As ADHD is associated with cardiovascular disease, modifiable cardiovascular risk factors could contribute to links between ADHD and premature mortality. Aims This study aims to investigate whether specific cardiovascular risk factors explain the association between childhood ADHD problems and a higher risk of premature mortality. Methods We used the UK 1958 birth cohort, the National Child Development study (NCDS), and linked death register data to examine whether children with ADHD problems at age 7 years were at higher risk of premature mortality by age 58 and if specific modifiable cardiovascular risk factors, measured at midlife (age 44 years), mediated this association using path analysis. Results A total of 8,016 individuals completed both the age 7 ADHD assessment and the age 44/45 biomedical assessment. Of these individuals, 231 (3.1%) were grouped as likely having ADHD. The odds ratio (OR) for deaths ( n = 251) in the ADHD group versus the non-ADHD group was 1.86 (95% CI 1.08–3.17). The risk was largely explained by cigarette smoking status at midlife and by a higher waist–hip ratio (a measure of obesity). Conclusions Childhood ADHD problems are associated with a higher risk of premature mortality by age 58. This risk seems to be mainly explained by two potentially modifiable cardiovascular risk factors: obesity and smoking. These risks should be prioritized for preventative interventions to reduce the risk of premature mortality in those with a history of ADHD.

Higher VLDL cholesterol linked to ~107% higher MI risk per 1-mmol/l increase.

VLDL cholesterol, rather than VLDL triglycerides, accounts for half of the myocardial infarction risk associated with apoB-containing lipoproteins, highlighting its primary role in atherogenesis.

The illusion of causality: instruments, colliders, and acute kidney injury in sepsis

Fergus Hamilton, Todd C Lee, George Davey Smith, Fernando P Hartwig, Guillaume Butler-Laporte; The illusion of causality: Instruments, colliders, and acute

For triglycerides, the restricted allele score was associated with CHD (OR 1.61; 95% CI 1.00-2.59) per 1-log unit increment, whereas the restricted allele score for HDL-C was not robustly associated (OR 0.91; 95% CI 0.42-1.98).

Genetic findings support a causal effect of triglycerides on coronary heart disease risk, while the causal role of HDL-C remains uncertain.

African-specific genetic loci determine iron status and risk of severe malaria and bacteremia in African children

Iron is essential for both humans and pathogens, yet its genetic regulation remains understudied in African populations. Here, we report genome-wide association studies of six iron-related biomarkers in 3928 children from five sites across Africa, with replication in 2868 African American adults and investigate associations with severe malaria and bacteremia. We identify previously unreported loci at genome-wide significance, for transferrin at GTF3C5, and for hepcidin at CHCHD7/SDR16C5. Variants tagging the DUP4 haplotype, encoding the Dantu blood group (rs552439837) are associated with soluble transferrin receptor levels. Variants at GTF3C5 (rs2905094) and DUP4 confer protection against severe malaria and bacteremia. The CHCHD7/SDR16C5 variant (rs73596248) increases hepcidin levels and is associated with reduced risk of Klebsiella pneumoniae and Staphylococcus aureus bacteremia. Polygenic risk scores derived from European data show limited transferability to African populations. In this work, we demonstrate new genetic insights into iron regulation and highlight iron's role in host-pathogen interactions.

Lowering VLDL cholesterol by 50% is linked to ~3% absolute ASCVD risk reduction.

Modeled reductions of VLDL cholesterol by 50% or 80% in individuals with elevated levels suggest a clinically meaningful 10-year absolute risk reduction of ASCVD in primary prevention.