DNA methylation as proxy of genetic, prenatal and perinatal psychiatric risk factors

Perinatal risk factors, DNA methylation and the development of ADHD symptoms: a high-dimensional mediation analysis

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.

The prenatal exposome and genome in predictive modelling of DNA methylation

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.

DNA methylation informs adult cardiovascular risk and prevention for low birthweight individuals

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.

Intergenerational epigenetic signatures of prenatal adversity and their role in emerging child psychopathology

Intergenerational and life-course links between a cardiovascular health-related methylation score and early vascular changes

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.

Methylation profile scores in child and adolescent health: a practical guide.

Methylation profile scores (MPSs) aggregate the effects of many DNA methylation (DNAm) sites across the genome into a single continuous value per individual. These scores are rapidly gaining traction in health research, as they translate DNAm patterns into summary measures that can be used to address many clinical and epidemiological questions. Most current research, however, is focused on adults, with little consideration given to transferability to children and adolescents. In this Review, we aim to provide a practical guide introducing MPSs and to discuss the current status of MPSs in child and adolescent populations. First, we introduce the diverse applications of MPSs, including the following: (1) use as exposure proxies to estimate exposures that are missing, under-reported, or hard to measure (eg, an MPS for exposure to maternal prenatal smoking); (2) use as biological proxies to summarise physiological processes such as inflammation (eg, an MPS for C-reactive protein); (3) use in risk stratification, where MPS variation is associated with risk of a future health outcome (eg, cardiometabolic disease); (4) use in diagnostics, where MPSs are used to detect disease states (currently most established for rare Mendelian syndromes and paediatric brain tumours); and (5) use in pharmacoepigenetics and treatment monitoring, an emerging area where MPSs are used to predict treatment response or track symptom change over time. Second, we outline specific considerations that apply to the developmental context, which explain why child and adolescent MPSs often differ from their later-life counterparts. Third, we provide recommendations on how to critically judge paediatric MPS studies. Finally, we conclude that, at present, with a few notable exceptions, most MPSs are better characterised as research tools at an early stage of development rather than clinical tools, and we highlight future directions for the field.