Genomics of Complex Traits: Methods and Applications

My dissertation covers a number of studies that seek to understand the genetics and functional basis of complex traits in either human or animal models. The first project is a genetic study of bipolar disorder using exome sequencing, primarily involving variant burden analysis and pathway analysis. The second project uses gene expression as a functional readout of a tissue system, which allows us to identify aging signatures in the eye. These two studies represent complementary approaches; while the first reflects inheritance patterns of DNA variants and phenotypes, and the second is a functional readout of an organ system. In the next two studies, I use a rat model involving both genetics and genomic tools to perform an integrative search for genes and functional pathways implicated in metabolic phenotypes. In this collaborative study, I combine multiple datasets including genotype-based QTL mapping and gene expression based functional comparison, seeking to triangulate signals that may be noisy or subtle in one platform alone. Along the way, I had to develop methodologies for data integration, and worked on solidifying existing resources—in this case, the rat reference genome. Mine is the beginning of a consolidated effort by the rat-genomics community to arrive at a more complete and accurate reference genome, so that the community can build on this improved resource for more accurate research in the future. As my studies have involved both genome and exome sequencing data, one of the challenges is to identify not only single nucleotide variants but also larger scale DNA copy number changes. Despite the many tools for calling copy number changes, there is still confusion about the proper investment of resources based on a principled power analysis. In my last chapter, I develop a basic mathematical framework that incorporates most of the important practical parameters impacting power, and create an online calculator and examples of some usage cases. Taken together, this dissertation is a reflection of how the field of genetics and genomics has moved in the last few years, involving rapidly advancing technology, and datasets with complex structures, requiring careful exploration and method development.PhDBioinformaticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/145925/1/sramdas_1.pd