Cancer arises from a complex interplay between genetic predisposition and environmental exposures. While genome-wide association studies (GWAS) have identified numerous genetic risk loci, these explain only a fraction of cancer heritability. Gene-environment (GxE) interactions are hypothesized to account for this “missing heritability,” but detecting them requires very large sample sizes and detailed data. The UK Biobank, with its large cohort (~500,000 participants), prospective design, whole-genome sequencing data, rich environmental information, and multi-modal imaging subset, provides an unprecedented opportunity to overcome the power limitations of previous studies and systematically identify these interactions.
Research Question:
How do specific genetic variants interact with environmental and lifestyle exposures to modify the risk of major cancers (lung, colorectal, breast, prostate, liver, pancreatic)?
Objectives:
To Identify Novel GxE Interactions: Conduct comprehensive genome-wide interaction studies (GWIS) to discover genetic variants that alter the effects of key exposures (e.g., smoking, alcohol, diet, air pollution) on the risk of major cancers.
To Investigate Biological Mechanisms: Utilize imaging-derived phenotypes (IDPs) from abdominal MRI, such as visceral adiposity and liver fat, as intermediate markers of organ pathology to understand the biological pathways through which GxE interactions contribute to cancer development.
To Improve Cancer Risk Prediction: Develop and validate integrated risk models that incorporate significant GxE interaction terms, aiming to improve risk stratification and identify high-risk subgroups for targeted prevention strategies.