Impact of Early life MetaBolic and psychosocial strEss on susceptibility to mental Disorders; from converging epigenetic signatures to novel targets for therapeutic intervention

Scientific abstract of the project

Nearly 40% of the EU population each year suffers from a mental disorder. Adverse experiences early in life can produce important physiological changes, which become embedded biological traces leading to increased vulnerability for later depression. There is now robust evidence indicating that early metabolic challenges impinge upon energy balance regulatory systems, which, in many cases, overlap with stress-response systems. EMBED will identify informative DNA methylation differences associated with prenatal psychological and metabolic stressors in genes that are relevant for mood disorders. These will be related to shared biomarkers to define common biological substrates between early life stress and maternal obesity for prevention and treatment. We will also determine whether intervention strategies can reverse such epigenetic marks and related biomarkers. The relationship between DNA methylation pattern in human peripheral samples (cord blood) and brain will be studied in animal models and brain post-mortem samples from depressive patients. EMBED brings together leading researchers with complementary expertise to exploit existing clinical data sets, including biomaterial collections from previous collaborative proposals, that will be analyzed in an original and innovative way to study the role of different, but often co-occurring, adverse prenatal conditions on individual risk/resilience to develop mental disorders in adulthood. This research may lead not only to a better understanding of the risk architecture of major psychiatric disorders, but could also enable preventive measures in risk populations, new diagnostics and, potentially, therapeutic approaches since, in contrast to genetic variations, epigenetic effects on the transcriptome may be reversed, also in adulthood.

Objectives

The primary objectives of this work are to:

1. Assess shared epigenetic mechanisms of maternal stress and maternal obesity through DNA methylation analysis and discovery in children born to stressed or obese mothers as well as adult post-mortem brains from people whose mothers were stressed or obese;
2. Test shared biological mechanisms mediating psychological stress and metabolic stress through metabolome and transcriptome analysis in two mother/infant cohorts;
3. Define the epigenetic signature of disease reversibility;
4. Delineate epigenetic signatures predicting high risk of depression for early prevention; and
5. Discover novel genes that respond both to maternal stress and maternal obesity.

As secondary objectives, the project aims to also:

1. Characterize the stability of methylation profiles of candidate genes between birth and later points in life; and
2. Establish the level of correspondence in methylation profiles of genes between brain and peripheral white blood cells at birth and later in life.

Layman summary

Extensive research on the biology of stress now shows that healthy development can be derailed by excessive or prolonged activation of stress response systems in the body and brain during fetal life. Such toxic stress exposure can have damaging effects on learning, behavior, and mental health across the lifespan. The consortium has been built to integrate basic researchers and clinicians to work on two very relevant cohorts (offspring of obese or stressed mothers) that will be here combined in a very innovative way to address specific questions on mental health risk factors and their potential prevention. One main concept is that maternal obesity during prenatal life can trigger similar responses to maternal stress, altering developmental trajectories and increasing the risk for mental health at adulthood. It is hypothesized that maternal stress might be accompanied by inappropriate nutrition patterns which could synergize in activating stress-response systems in the developing organism. These adverse experiences can increase the likelihood of developmental delays and later health problems, including heart disease, diabetes, and depression.

This consortium will assess whether common biological signals characterise early exposure to metabolic and psychological stress, affecting the long-term expression of genes involved in brain as well as in immune-metabolic function, triggering mental disorders. A special emphasis will be given to long-lasting epigenetic modifications, which could alter context- and time-dependent expression of genes relevant for brain function as well as peripheral hormones, cytokines or adipokines, indices of immune-metabolic function, that might be used in the clinic for disease prevention and health promotion during pregnancy.

Project publications