Genetic susceptibility shaped by biological state: beyond gene-environment interaction.

This mini-review proposes a state-aware approach for interpreting gene-environment interaction (G × E). Biological state is the internal condition in which genetic susceptibility becomes functional. A measured exposure may precede that state, reflect it, incompletely measure internal dose or response, or trigger transition into it. A genotype-by-exposure interaction may therefore be statistically valid but mechanistically ambiguous when the measured exposure does not identify the condition that shapes susceptibility. Genetic effects on gene regulation may appear only after immune stimulation, within specific cell states, or in diseased tissue, supporting biological state as a condition of variant function. At the individual level, susceptibility may emerge during infection, puberty, insulin resistance, inflammatory activation, hormonal transition, or biological ageing. State-aware analysis requires investigators to define what the exposure represents in relation to host biology, measure the relevant state with spatial and temporal specificity, and evaluate replication across comparable biological contexts. This approach moves G × E interpretation from exposure-defined interaction toward biological-state precision in genetic epidemiology.