Aug 2026· Journal of Global Health· Vol 16· 0 citations· 53 references
Medicine
TL;DR
The Barker-consistent hypothesis-free discovery approach identified novel and known candidate genes that, with future validation, may serve as therapeutic targets, identify high-risk individuals, and support clinical trial recruitment.
Abstract
Background Barker’s hypothesis posits that adverse in utero exposures, often reflected by low birthweight, increase adult cardiovascular disease (CVD) risk. However, underlying mechanisms remain unclear; identifying potentially causal mediators is crucial for developing effective interventions. Emerging research suggests epigenetic modifications may influence CVD traits from early life. We aimed to identify DNA methylation (DNAm) signatures that mediate birthweight and CVD traits and to establish their biological relevance across three developmental time points using multi-omics integration. Methods We identified DNAm mediators using epigenetic Mendelian randomisation (MR). The exposures were 261 birthweight-associated CpG sites (BW-CpGs) from epigenome-wide association studies, instrumented by cis-methylation quantitative trait loci (cis-mQTLs) in European-ancestry participants from the Accessible Resource for Integrative Epigenomic Studies measured at three developmental time points: birth (mean gestational age = 40 weeks), childhood (mean age = 7.49 years), and adolescence (mean age = 17.14 years). The outcomes included adult cardiovascular events and lipid traits from genome-wide association studies (n = 98,048–547,261). Sensitivity analyses included colocalisation, Steiger’s test, Cochran’s Q, and pleiotropy-robust methods. We interrogated DNAm persisting across development using omics datasets. Results Using cis-mQTLs measured at birth, we found 230 associations between 216 BW-CpGs and CVD traits, including coronary artery disease, hypertension, stroke, cholesterol, and triglycerides (false discovery rate-corrected P < 0.05), with effect size directions consistent with Barker’s hypothesis. A total of 42 associations were robust following sensitivity analyses. Persistent DNAm changes across development were observed at ASGR1 and KDM2B. Multi-omics interrogation prioritised a promising therapeutic candidate (ASGR1). Conclusions Although Barker’s hypothesis is well-established, this is the first study to explore its causal pathway using a rigorous, multi-time-point epigenetic MR framework with multi-omic integration. This represents a major advancement over previous observational and DNAm studies. The Barker-consistent hypothesis-free discovery approach identified novel and known candidate genes that, with future validation, may serve as therapeutic targets, identify high-risk individuals, and support clinical trial recruitment.
It is found that genomic associations with cord blood DNAm are stronger and more widespread than prenatal exposures, although typically, the prenatal exposome explains additional variation in DNAm beyond genetic influences.
Rosa H. Mulder, Elena Isaevska, C. Cappadona et al.· bioRxiv· 0 citations
An LE8-derived DNAm score was associated with lower cIMT across the life course and, to a lesser extent, across generations, suggesting that blood DNAm reflects cumulative cardiovascular health and vascular burden and may complement conventional cardiovascular risk assessment.
B. Mishra, E. Raitoharju, L.-P. LyytikaÌinen et al.· medRxiv· 0 citations
Background. Cord blood DNA methylation profile scores (MPSs) based on genetic and pre-/perinatal risk factors for neurodevelopmental conditions (NDCs) may capture downstream biological effects and help understand how combined exposure signals contribute to NDC risk. Methods. Using data from two longitudinal birth cohorts, Generation R (N-train = 1856, N-test = 476) and ALSPAC (N-validation= 832), we developed cord blood MPSs based on genetic and pre-/perinatal NDC risk factors. We assessed individual and combined predictive performance of risk factors and MPSs for eight childhood psychiatric outcomes (four broad, four specific), measured between ages 5 and 14 years. We also evaluated if the MPSs could be combined into a composite "transmission load" MPS. Results. We validated four novel MPSs: maternal age, birthweight, and genetic liability for ADHD and schizophrenia (r range = 0.08 to 0.29) and included two previously validated MPSs: maternal smoking and gestational age (r range = 0.42 to 0.63). Jointly modeling the six MPSs with their corresponding risk factors explained on average 3.3% of variance in outcomes, higher than that explained by risk factors (1.8%) or MPSs alone (1.6%), indicating complementary sources of risk. The "transmission load" MPS did not replicate due to heterogeneous contributions of the predictors across cohorts. Conclusions. The four novel MPSs based on genetic and pre-/perinatal risk factors can serve as valuable tools for future research. Integrating genetic and prenatal risk factors with DNA methylation at birth can provide insights into their individual and joint contributions to early psychiatric risk and may improve prediction.
Elena Isaevska, Rosa H. Mulder, Isabel K. Schuurmans et al.· medRxiv· 0 citations
Importance: Epigenetic age acceleration (EAA) has been linked to increased disease risk in adults, yet its developmental trajectories and early-life neighborhood determinants remain poorly understood. Objective: To examine associations between the neighborhood exposome at birth and EAA trajectories from early childhood through adolescence. Design, Setting, and Participants: Longitudinal cohort study using data from Project Viva, a pre-birth cohort that enrolled pregnant women in eastern Massachusetts (1999-2002). Participants included 570 children with available peripheral blood DNA methylation data, complete neighborhood characteristics, and complete covariates. Data were analyzed from 2024 to 2026. Exposures: Neighborhood exposome profiles at birth derived from 22 census tract-level characteristics across four domains (area deprivation, social fragmentation, population density, and environmental quality) using self-organizing maps. Main Outcomes and Measures: EAA was calculated at ages 3 (n=84), 8 (n=301), and 13 (n=434) years using Horvath, Skin & Blood, and Wu epigenetic clocks. Trajectories were identified using latent class linear mixed models. Associations between neighborhood profiles and EAA trajectories were estimated using multinomial mixed models. Results: Among 570 children (mean [SD] age at early childhood, 3.2 [0.4] years; 265 [46.5%] female), three EAA trajectory groups (stable, increasing, and decreasing for the Horvath and Skin & Blood clocks or low-baseline for the Wu clock) and three neighborhood profiles were identified. Compared with Profile 1 (suburban, lowest adverse exposures; n=278), children born into Profile 2 (urban, high residential instability and single-person households, and highway proximity; n=168) had greater odds of increasing EAA for Wu clock (aOR, 1.67; 95% CI, 1.03-2.69). Profile 3 (urban, high socioeconomic deprivation; n=124) showed no significant associations. Conclusions and Relevance: In this longitudinal cohort study, birth into neighborhoods characterized by high residential instability and single- person households, and highway proximity was associated with increasing Wu EAA trajectories across childhood. These findings suggest that early-life neighborhood conditions, encompassing both social and physical environmental factors, may represent targets for interventions aimed at reducing long-term disease risk. Further research is needed to clarify the implications of these findings for later health and prevention.
Q. Yuan, A. Bozack, V. Paquin et al.· medRxiv· 0 citations
Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with perinatal and genetic risk factors, including prenatal maternal smoking, pre-pregnancy BMI, gestational age, birth weight, and common genetic variants. These risk factors, as well as ADHD symptoms themselves, have previously been linked to cord blood DNA methylation (DNAm). We tested the hypothesis that cord blood DNAm mediates the effects of these risk factors on ADHD symptoms. Methods: Participants were drawn from two large European population-based cohorts: the Generation R Study and Avon Longitudinal Study of Parents and Children (n=3087). Cord blood DNAm was assessed using Illumina 450k and EPIC v1 arrays. ADHD symptoms were repeatedly measured with parent-based questionnaires between the ages 6 and 10 years. A high-dimensional mediational model based on DNAm principal components mediation analysis (PCMA) estimated the global mediation effect of all tested DNAm sites. Mediation via single principal components and individual DNAm sites was also evaluated using structural equation modeling and Divide-Aggregate Composite-null Test (DACT). Results: DNAm globally mediated the relationships of maternal smoking, low birth weight, and an ADHD polygenic score (PGS) with ADHD symptoms. Specifically, DNAm explained 62% of the total effect for maternal smoking, 56% for birth weight, and 35% for the ADHD-PGS. No association with individual principal components or single DNAm sites survived multiple testing correction. Evidence for mediation was absent for pre-pregnancy BMI and inconsistent for gestational age. Conclusions: In this first epigenome-wide mediation study of ADHD, we demonstrate a role of DNAm at birth in mediating the association of maternal smoking, birth weight and ADHD-related genetic variants with ADHD symptoms. However, lack of individual site-specific findings and the observational design limit causal biological interpretations. We therefore encourage further research of epigenetic pathways for these three risk factors.
A. Neumann, M. Suderman, J. Felix et al.· medRxiv· 0 citations