A cross-population compendium of gene-environment interactions

Area of Science:

• Genetics
• Genomics
• Environmental Health

Background:

• Gene-environment interactions (GEI) are crucial for understanding phenotypic plasticity.
• Previous studies have been limited in scope and population diversity.

Purpose of the Study:

• To create a comprehensive atlas of GEI across diverse populations.
• To investigate the etiological factors contributing to GEI, including lifestyle and reverse causality.
• To explore the impact of GEI on heritability, polygenic prediction, and drug development.

Main Methods:

• Cross-population genome-wide analyses of 440,210 individuals (European, Japanese) with replication in 539,794 diverse individuals.
• Decomposition of GEI contributions from age, sex, and lifestyle factors.
• Single-cell projection and omics-level analyses to identify cellular and molecular mechanisms.

Main Results:

• Uncovered missing heritability and novel trait-trait relationships driven by synergistic genome-environment effects.
• Demonstrated systematic impacts of GEI on polygenic prediction accuracy and cross-population portability.
• Identified aging-related shifts in genetic regulatory pathways and sex-discordant genetic effects in lipid metabolism.

Conclusions:

• This study provides a detailed map of GEI, enhancing our understanding of complex trait biology.
• Findings offer critical insights for personalized medicine and optimizing drug development, particularly by explaining clinical trial failures.
• The research highlights the dynamic nature of genetic associations and their environmental modulation.