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

Area of Science:

• Genetics and Epidemiology
• Molecular Biology
• Bioinformatics

Background:

• Gene-environment interaction (G × E) is crucial for understanding disease etiology.
• Current G × E interpretations can be mechanistically ambiguous when biological state is not considered.
• Genetic susceptibility's functional state is influenced by internal biological conditions.

Purpose of the Study:

• To propose a state-aware framework for interpreting gene-environment interactions (G × E).
• To enhance the mechanistic understanding of G × E by integrating biological state.
• To improve precision in genetic epidemiology by focusing on biological context.

Main Methods:

• Reviewing existing literature on G × E and biological state.
• Defining biological state as the internal condition for genetic susceptibility.
• Proposing a framework that considers the temporal and spatial relationship between exposure and biological state.

Main Results:

• Identified limitations in current G × E analysis due to unmeasured biological states.
• Demonstrated that genetic effects can be state-dependent (e.g., immune stimulation, cell states, disease).
• Highlighted specific life stages and conditions where susceptibility emerges (e.g., puberty, insulin resistance, aging).

Conclusions:

• A state-aware approach is necessary for accurate G × E interpretation.
• Future G × E research should define exposures relative to host biology and measure relevant states.
• This framework promotes a shift towards biological-state precision in genetic epidemiology.