Does phenotypic age acceleration (PhenoAgeAccel) independently predict the incidence of skin and subcutaneous tissue disorders (SSTDs) in the UK Biobank cohort, and to what extent does it interact with inherited genetic susceptibility-quantified via polygenic risk scores (PRS)-to shape disease risk?
Objective:
This project seeks to comprehensively examine the interplay between biological ageing and genetic predisposition in the development of SSTDs. Specifically, we aim:
1. To quantify the association between PhenoAgeAccel and the risk of incident SSTDs after adjusting for demographic, lifestyle, and environmental factors.
2. To construct and validate PRS for major SSTD subtypes and evaluate their independent contribution to disease incidence.
3. To test both multiplicative and additive interactions between PhenoAgeAccel and PRS in determining SSTD risk.
To conduct mediation analyses assessing whether PhenoAgeAccel mediates the impact of environmental exposures (e.g., UV radiation, smoking) on SSTD onset.
Scientific rationale:
PhenoAgeAccel, a validated biomarker of biological ageing derived from nine routine serum chemistries, captures molecular ageing heterogeneity beyond chronological age. Concurrently, PRSs integrate the cumulative burden of common genetic variants influencing skin pathology. While both domains have been independently linked to health outcomes, little is known about their joint contributions to SSTDs. This project addresses a critical gap by integrating molecular ageing signatures with inherited genetic risk to uncover gene-ageing-environment interactions. These insights will advance mechanistic understanding of cutaneous ageing and disease, enable precision risk stratification, and highlight targets for prevention and intervention.
