Research Question
Multimorbidity is a major global health challenge. Family history (FH) and polygenic risk scores (PRS) both predict disease risk, yet their independent and combined effects on multimorbidity and its age at onset remain unclear. Some individuals also show “decoupling,” in which clinical outcomes diverge from familial or genetic risk. This project investigates: (1) the independent and joint effects of FH and PRS on multimorbidity risk and onset; (2) the mediating or modifying role of circulating proteomic and metabolomic profiles; and (3) factors underlying decoupling between FH/PRS and multimorbidity.
Research Objectives
(1) Quantify the relative and combined contributions of FH and PRS to multimorbidity risk and onset using UK Biobank data.
(2) Integrate FH, PRS, and plasma multi-omics to identify mediators and modifiers of multimorbidity.
(3) Characterize molecular signatures of “decoupled” individuals to reveal resilience or vulnerability factors.
(4) Generate evidence to support precision prevention strategies tailored to familial, genetic, and molecular risk.
Scientific Rationale
Clarifying how FH and PRS jointly influence multimorbidity will improve understanding of genetic and familial contributions to complex disease accumulation. Multi-omics integration can identify pathways mediating these effects and distinguish causal mechanisms from downstream markers. Investigating decoupling will reveal biological or environmental factors shaping heterogeneity in disease penetrance, informing targeted prevention and early intervention.