We will obtain genome-wide white blood cell methylation data on 1000 mother-child pairs in the Avon Longitudinal Study of Parents and Children. Mothers' DNA was obtained during pregnancy and 18 years later and offspring DNA from cord blood, at age 7 and age 15-18. Genome-wide SNP data are available on all participants and the children of the 1000 mother-child pairs taken included in the present proposal have CNV analysis and genome-wide gene expression data available and whole genome exon sequencing is in progress. 2000 of the offspring will have whole genome exon sequencing, CNV analysis and genome-wide gene expression data. Dense phenotyping on the mothers and their offspring has been completed, with exposure and outcome measures relevant to cognitive development, growth, behavioural patterns, metabolic health and detailed functional, physiological and biochemical assessments. The generation of DNA methylation data will provide unparalleled opportunities for the integration of multi-dimensional biological data in human samples for the benefit of the scientific community. Stored samples of blood, hair, teeth, placentas, umbilical cords and urine are available for further analysis. These data will be curated and made fully available to the scientific community. The resource will address the issue of healthy human development (the cohort are currently in early adulthood) and, in the mothers, the avoidance of age-related decline.

Due to the poor accessibility and availability of DNA from human tissues we will complement the proposed resource with tissue-specific methylation and gene expression analysis in animal (rodent) models (incuding those with diet-induced altered ageing trajectories) which will include WBC DNA methylation to facilitate a direct comparison of WBC epigenetic signatures to those of target tissues. Rodent tissues will be banked and available to undertake fine mapping methylation analysis and gene expression studies of differentially methylated regions identified through analysis of ALSPAC data.

Resource development will be complemented by an overarching bioinformatics arm that will ensure the integration of respective data sets and the development of accessible data formats.. We will also integrate the resource with the Human International Epigenome Consortium (IHEC) to ensure maximal utilisation and added value for the data.

1. Strategic Relevance

Epigenetic studies of readily obtainable material are becoming a central focus of biological research internationally. Epigenetic profiles can serve as exposure markers and as prognostic or predictive biomarkers. ALSPAC is a unique resource in having two-generational data and cord blood samples available, allowing for intrauterine influences, intergenerational transmission, change in methylation from birth through to pre-pubertal and post-pubertal age, and investigation of how methylation patterns predict and change with development. This resource, coupled with studies of the relationship between white cell and other tissue methylation, would be unequivocally world leading.

This resource provides an excellent match with the current "BBSRC Priorities" document. Under "Ageing Research: Lifelong Health and Wellbeing" it is stated that "Evidence increasingly suggests that impaired growth in utero especially when followed by rapid post-natal growth can seriously impair many aspects of health and may influence ageing. The mechanisms by which these early life exposures are mediated are poorly understood. There is a need to encourage research that investigates how early developmental factors may influence health during ageing. Specifically, the challenges are to understand i) how nutritional (and other) exposures are recorded and transmitted through subsequent generations of cells and ii) how this "memory" is translated into altered function in later life." Our study will directly allow these issues to be addressed. In "The Age of Bioscience: Strategic Plan 2010-2015" the 3rd strategic research priority is "Basic Bioscience underpinning health", which the proposed resource will directly address, including the "key research goal [which] is to develop a better understanding of the role of diet and physical activity and the mechanisms by which they affect development and health" and the key priority to "establish greater understanding of how diet affects health throughout life, including epigenetic effects".