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

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

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.

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 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.

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.

Epigenetic clues: Predicting maternal depression through DNA methylation.

707. Promises and pitfalls of DNA methylation and miRNA for stratification and treatment optimization: two sides of one coin

Abstract Background DNA methylation and micro-RNA (miRNA) both act as gene-regulatory mechanisms. Their merit and challenge are two sides of the same coin: they respond to the environment and show the impact of longitudinal processes such as response to treatment and recovery from illness at the molecular level. However, it remains challenging to disentangle the ‘desired’ exposure of the whole environment, particularly in the context of psychiatric disorders. For DNA methylation and miRNA to become aids for stratification and markers of treatment response for depression, multiple analysis strategies are required to address this problem from multiple angles. Aims & Objectives We give an overview of current analysis strategies and present published and unpublished results to show how these molecular markers can contribute to useful stratification of patients with depression. Method For this purpose, a combination of methods is typically required and most informative. We discuss differential analyses for DNA methylation and miRNA in response to treatment and environmental exposure, such as specific kinds of trauma. We also show the merit of methods integrating DNA methylation information in the form of DNA-methylation-based immunological cell type estimates, ‘immunomethylomics, the application of overall DNA methylation variability, and DNA-methylation clocks. Results We present published and unpublished results that show how DNA methylation and miRNA, as gene-regulatory mechanisms, can contribute to useful stratification and early optimization of treatment and treatment response in patients with depression. We highlight the application of immunomethylomics and DNA methylation in the prediction of treatment response and symptom improvement in samples treated with ketamine and augmentation with celecoxib. Furthermore, we show how different kinds of trauma and exposure can impact both DNA methylation at the CpG level and beyond, as well as miRNA. The methods and their results that we present can also be extrapolated to other psychiatric disorders. Discussion & Conclusions In this presentation, we discuss the latest insights on the response of DNA methylation to treatment, e.g., personalized response-guided dosing with ketamine. We then extend towards analysis strategies that combine DNA methylation markers, such as immunomethylomics, overall DNA methylation variability, etc., as well as distinct signatures of miRNA depending on the environmental exposure. We discuss published and unpublished results that show the potential of DNA methylation and miRNA as gene-regulatory mechanisms. Overall, we can show that miRNA and DNA methylation as molecular markers involved in gene regulation are promising to stratify patients in response to treatment and other environmental exposures.