Overview

This multidisciplinary project will assess the impact of adverse and positive early life stimuli and exposure to social, environmental and biological signals over the life course on DNA methylation profiles, linking the findings to functional health trajectories. The study will explore existing and newly generated DNA methylation profiles in samples from eight UK population-based cohorts.

DNA methylation signatures of early life events and exposures over the life course

Epigenetic signals are malleable and can change in response to internal and external stimuli. The epigenome thereby provides a mechanism of interaction between the genome and the environment. We hypothesize that early life stimuli and exposures over the life course leave an epigenetic mark. 

We will perform prospective analysis of longitudinal data to explore DNA methylation in samples from four British cohort studies in order to identify epigenetic signatures of early life experience and exposure to social, environmental and biological stimuli over the life course, linking findings to changes in physical and cognitive function during ageing, with the intention to:

• Establish whether biological, environmental and social stimuli in early life and over the life course result in detectable differences in DNA methylation profiles in adults, by testing for epigenetic associations with biological,environmental and social factors in utero, in early childhood, and later life.

• Assess whether there are differences between cohorts in DNA methylation patterns, comparing samples containing individuals born in different years (1946, 1958 and 1970) accounting for age.

• Explore the role of epigenetics in healthy functional ageing. We will compare epigenetic signatures to longitudinal functional health trajectories throughout life, across cohorts, across cell types (blood and buccal) and across different age categories. We will also explore whether DNA methylation signatures of early life experiences can mediate functional ageing trajectories (such as cardiovascular, lung and cognitive function) and whether they can be reversed in response to social and environmental exposures in later life.

• Apply a new approach to estimate biological age, the epigenetic clock, to assess the rate of epigenetic ageing and relate it to early life stimuli and longitudinal biomedical, social and environmental trajectories.

Proof of concept analyses

Additional analyses in subsamples will include DNA methylation profiling at multiple time-points to estimate reversibility of DNA methylation, cross-tissue comparison across blood, buccal and additional tissues, and gene expression
analysis for functional interpretation. The findings will establish the feasibility of our approach by combining samples of participants across each of four discovery UK population-based cohorts into a large cross-cohort sample well powered to determine the influence of early life factors on epigenetic signatures throughout the life course. Replication of the findings will be pursued in samples from four additional cohorts. Taken together, the overall findings will be based on DNA methylation profiles from 8,000 samples across eight UK population cohorts.

Future extensions of analyses and developing the epigenetic network

The proof of concept approach will allow such analyses to be extended to larger samples within cohorts by forming the basis for further funding applications and establishing an epigenetic research network across UK population-based cohorts.

Resources

Analysis will be based on existing and newly generated DNA methylation data from 4 longitudinal UK cohort studies:

• National Survey for Health and Development (NSHD) or 1946 birth cohort
• National Child Development Study (NCDS) or 1958 birth cohort
• 1970 British Cohort Study (BCS70)
• TwinsUK cohort (TwinsUK)

The findings will be replicated in a further four longitudinal UK cohorts studies:

• Avon Longitudinal Study of Parents and Children (ALSPAC)
• Lothian Birth Cohort 1921 (LBC1921)
• Lothian Birth Cohort 1936 (LBC1936)
• Hertfordshire Cohort Study (HCS)