* Setting the Stage for TEMPO *
We laid out the rationale for TEMPO through expert commentaries and opinion pieces reflecting on progress, challenges, and current research priorities within the field. We also systematically reviewed research examining how epigenetic patterns relate to differences in brain structure and function - an new field called Neuroimaging Epigenetics. We found that over 80% of existing studies in this area have focused on adults, are cross-sectional, use single datasets and rely on modest sample sizes. Based on these findings, we took the initiative to establish a new consortium - the Methylation, Imaging, and NeuroDevelopment (MIND) Consortium – to address these unmet needs and advance our understanding of DNA methylation-brain dynamics during development and their implications for psychiatric risk.
* Aim 1: WHAT - Characterizing Epigenetic Timing Effects on Child Mental Health *
Pooling together data from 33 cohorts, we have revealed new insights into the temporal relationship between DNA methylation and child health outcomes. We find that for most (neuro)developmental outcomes examined (especially ADHD), DNAm at birth is indeed a more significant predictor than when measuring DNAm during childhood. In contrast, the opposite was observed for BMI. Overall, we find that epigenetic signals are highly temporally-specific: what we see at one time point may thus be missed if we measure epigenetic markers at a different time point. This highlights the necessity of considering the time-varying nature of DNAm in epigenetic research and confirm the existence of epigenetic timing effects on child (mental) health – the core hypothesis of TEMPO.
* Aim 2: WHERE - Locating Epigenetic Timing Effects with Greater Precision *
DNAm patterns differ between cell-types. This raises the possibility that the epigenetic timing effects we observe reflect the use of different tissues, and intriguingly, that cell-types found specifically in cord blood at birth may show greater potential than others in predicting mental health outcomes. To address this and in collaboration with an international team of partners, we have built the first cell-type estimation panel that can be applied to epigenetic data collected from blood at any time point in the lifecourse, in order to enhance our ability to isolate developmental changes (from technical sources of noise) in longitudinal epigenetic analyses and to study the influence of cell-type composition at different ages on epigenetic-health associations.
* Aim 3: WHY - Identifying the Genetic and Environmental Origins of Epigenetic Timing Effects *
Our third objective is to develop an explanatory model of epigenetic timing effects on mental health, in order to elucidate etiological pathways and pinpoint new targets for prevention. So far, we have laid the groundwork for this aim by, first, examining how genetic liabilities and environmental factors individually associate with DNAm. Notably, we find that genetic liability for neurodevelopmental conditions - and especially schizophrenia - is detectable in neonatal DNAm already at birth (i.e. pre-symptom onset) and within the general population. At the same time, we find that prenatal environmental factors, such as maternal smoking and BMI, also explain a large proportion of variability in DNAm patterns at birth. As a next step, we plan to extend this work by applying trio genetic designs (involving genetic data on mothers, fathers and offspring) to better disentangle the contribution of genetic vs environmental influences on offspring DNAm.
