Decoding the functional roles of genetic variants in complex phenotypes

There is more to the information content of DNA than the simple linear sequence of the polymer chains. Understanding genetic risk for the development of complex disease requires an understanding of the different levels of information that are present within the genome. Components of this information are captured in the structure of the DNA within cells. We contend that disease associated genetic variants provide landmarks for decoding the higher dimensional data within genomes. Our recent work addresses how inter-genic variants contribute to complex phenotypes. Using an analytical pipeline that incorporates three-dimensional chromatin structure and RNA expression data, we have begun to untangle the functional impact of regions containing diabetes and obesity SNPs. We have extended our analyses to ~1300 complex phenotypes and have identified co-morbid relationships between these complex polygenic disorders. We have also identified a role for mechanotransduction in the realization of cell exposure contributions to these complex regulatory relationships.