Periodic Reporting for period 1 - TEMPO (Solving the 'time puzzle' of epigenetic effects on child mental health)
Período documentado: 2022-06-01 hasta 2024-11-30
Recent studies have shown that common mental health problems in children are associated with epigenetic patterns at birth. Epigenetics involves mechanisms that regulate gene activity in response to genetic and environmental influences. Curiously, this association is ‘lost’ when measuring the same epigenetic patterns later in development. This discovery is highly unexpected and potentially groundbreaking: the existence of epigenetic timing effects could lead to new insights into the origins of mental health issues and open much-needed opportunities for early risk detection. However, what factors drive these timing effects, how they manifest, and why they occur is currently unknown.
TEMPO aims to solve the epigenetic 'time puzzle' of child mental health by combining innovative, multidisciplinary approaches and generating new data in longitudinal European cohorts. Our objectives are to: 1) Systematically characterize unknown properties of epigenetic timing effects, including their genomic scale, specificity to mental health, and persistence into adulthood, using advanced quantitative methods. 2) Locate epigenetic timing effects with greater precision by establishing whether effects are driven by epigenetic patterns in specific tissues and cell types found at birth but not later in life. 3) Explain epigenetic timing effects by disentangling their genetic and environmental origins, drawing on the power of genetically sensitive designs.
In addition to leading a breakthrough in the field of psychiatric epigenetics and addressing a major knowledge gap at the intersection of biological and psychological sciences, TEMPO has the potential to set in motion a paradigm shift in how we conceptualize, understand, and approach child mental health.
TEMPO aims to solve the epigenetic 'time puzzle' of child mental health by combining innovative, multidisciplinary approaches and generating new data in longitudinal European cohorts. Our objectives are to: 1) Systematically characterize unknown properties of epigenetic timing effects, including their genomic scale, specificity to mental health, and persistence into adulthood, using advanced quantitative methods. 2) Locate epigenetic timing effects with greater precision by establishing whether effects are driven by epigenetic patterns in specific tissues and cell types found at birth but not later in life. 3) Explain epigenetic timing effects by disentangling their genetic and environmental origins, drawing on the power of genetically sensitive designs.
In addition to leading a breakthrough in the field of psychiatric epigenetics and addressing a major knowledge gap at the intersection of biological and psychological sciences, TEMPO has the potential to set in motion a paradigm shift in how we conceptualize, understand, and approach child mental health.
* 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.
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.
The TEMPO project has generated new insights that extend well beyond the current state of the art, challenging existing paradigms in epigenetic epidemiology, which heavily rely on single DNAm assessments. Key results beyond the state of the art include: (i) the finding that epigenetic signals are temporally distinct and differentially associated with health outcomes. This holds key implications for research and future potential clinical applications. By identifying critical periods when epigenetic patterns are most predictive of mental health outcomes, we may also be able to enhance timely detection of risk before the emergence of mental health problems and inform the development of early intervention strategies. (ii) The newly established MIND Consortium significantly advances neuroimaging epigenetics, pooling data from over 5,000 individuals (compared to typical studies with fewer than 100). This collaborative network will facilitate powerful interdisciplinary studies and set best-practice standards through open science protocols. (iii) Our development of a "lifecourse" blood cell-type estimation panel represents a methodological leap forward, enabling researchers to better differentiate tissue-specific versus developmental timing differences epigenetic analyses. In turn, this can provide new clues about biological mechanisms and potential therapeutic targets. (iv) Finally, the discovery that genetic liability to neurodevelopmental disorders - including schizophrenia - associates with DNAm patterns already at birth (years before phenotypic manifestation) in the general population provides new clues about the biological correlates of genetic risk factors in early life. Our work also illustrate how the combination of genetic and epigenetic data at birth may enhance prediction models of neurodevelopmental risk.