The Epigenomics Program and the Biology of Adversity Project at the Broad Institute are looking to discover biomarkers of exposure (e.g. stress, lifestyle, environmental exposure, healthy history etc) that predispose individuals to disease and reduced health span. The biological pathways linking long-term stress exposure to disease onset remain poorly defined. We aim to leverage UK Biobank data to identify robust, biologically meaningful biomarkers of exposure that can elucidate mechanisms of disease vulnerability. This research will integrate diverse data modalities, with three areas of focus. First, we will harness the UK Biobank’s extensive and diverse participant metadata to examine how variables such as socioeconomic status, early-life adversity, lifestyle factors, and ethnicity intersect with exposure and disease trajectories. This approach ensures inclusivity and improves the generalizability of biomarker discovery across populations. Second, we will utilize high-resolution proteomic data (including Olink and plasma proteomics) to investigate circulating peptide hormones involved in the hypothalamic-pituitary-adrenal (HPA) axis. Particular attention will be given to hormones such as cortisol, ACTH, and CRH, which are central to the stress response. By correlating hormone profiles with stress exposure histories, we aim to identify proteomic signatures reflective of chronic HPA axis activation. Third, we will analyze genome-wide DNA methylation patterns to detect gene-specific epigenetic modifications associated with exposure. Methylation signatures will be mapped to genes involved in stress signaling, immune response, and metabolic regulation, allowing us to explore how environmental stressors become biologically embedded and influence gene expression. These efforts will reveal biomarkers spanning social, proteomic, and epigenetic domains that mediate the effects of chronic stress on health, paving the way for early detection tools and preventive strategies.
