Leveraging GWAS and the Transcriptome to Identify Potential Causal Genes in Osteoporosis

Osteoporosis is the most common disease affecting bone and is considered a major societal health problem implicating the lives of millions of individuals in the United States and across the globe. Over the past 15 years, Genome-wide Association Studies (GWASs) have identified a large number of variants influencing Bone Mineral Density (BMD), the single best predictor of osteoporosis fracture. Post-GWAS efforts are attempting to identify the genes responsible for the effects of the reported variants. Most of the variants identified by GWAS exert their impact on bone by altering gene regulation. In my dissertation work, I aimed to prioritize previously identified genetic associations, from humans, using novel, unbiased approaches. In the first chapter, I highlighted how molecular “-omics” data and cutting-edge analytical approaches are being used to facilitate gene discovery from GWAS and “make sense” of these studies. I also discussed resources that are needed in the bone field and novel approaches that have been used in my graduate work and the potential for their improvement in coming years. In the second chapter, I focused on identifying potentially causal long non-coding RNAs, an understudied population of non-coding RNAs in the context of bone and osteoporosis. I was able to identify eight lncRNAs as potentially causal in osteoporosis and are candidates for experimental follow-up studies. In the third chapter, I leveraged long-read proteogenomics to identify potentially causal protein-coding isoforms in osteoporosis. I provided a list of potentially causal isoforms and functionally validated TPM2 in vitro. Finally, I shared my final thoughts on the state of the field and future directions for the next generation of systems geneticists who aspire to provide treatment for osteoporosis. Ultimately, this dissertation contributed to our understanding of the genetic architecture of osteoporosis-related traits and presented new approaches to follow-up on GWAS studies more generally.