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Studies of gene-environment (GxE) interactions describe how genetic and environmental factors influence the risk of developing disease. Intermediate (molecular or clinical) phenotypes (IPs) are traits or metabolic biomarkers that mediate the effects of gene-environment influences on risk behaviors. Functional systems genomics discovery offers mechanistic insights into how DNA variations affect IPs in order to detect genetic causality for a given disease. Disorders of body composition include obesity (OB), Type 2 diabetes (T2D), and osteoporosis (OSTP). These pathologies are examples of how a GxE interaction contributes to their development. IPs as surrogates for inherited genotypes play a key role in models of genetic and environmental interactions in health outcomes. Such predictive models may unravel relevant genomic and molecular pathways for preventive and therapeutic interventions for OB, T2D, and OSTP. Annotation strategies for genomes, in contrast to phenomes, are well advanced. They generally do not measure specific aspects of the environment. Therefore, the concepts of deep phenotyping and the exposome generate new avenues to exploit with high-resolution technologies for analyzing this sophisticated phenome. With the successful characterization of phenomes, exposomes, and genomes, environmental and genetic determinants of chronic diseases can be united with multi-OMICS studies that better examine GxE interactions.

Mini-Review: The Contribution of Intermediate Phenotypes to GxE Effects on Disorders of Body Composition in the New OMICS Era