Pathogenesis of complex diseases involves the integration of genetic and environmental factors over time, making it particularly difficult to tease apart relationships between phenotype, genotype, and environmental factors using traditional experimental approaches.

Using gene-centered databases, we have developed a network of complex diseases and environmental factors through the identification of key molecular pathways associated with both genetic and environmental contributions. Comparison with known chemical disease relationships and analysis of transcriptional regulation from gene expression datasets for several environmental factors and phenotypes clustered in a metabolic syndrome and neuropsychiatric subnetwork supports our network hypotheses. This analysis identifies natural and synthetic retinoids, antipsychotic medications, Omega 3 fatty acids, and pyrethroid pesticides as potential environmental modulators of metabolic syndrome phenotypes through PPAR and adipocytokine signaling and organophosphate pesticides as potential environmental modulators of neuropsychiatric phenotypes.

Identification of key regulatory pathways that integrate genetic and environmental modulators define disease associated targets that will allow for efficient screening of large numbers of environmental factors, screening that could set priorities for further research and guide public health decisions.