Genetic Methods and Studies of Human Growth and Development Across the Allelic Spectrum

Genetics is an incredibly powerful tool for interrogating human biology, as it allows us to identify genes influencing biological processes and diseases in a hypothesis-free manner and in the context of the human body. The discovery of these genes can also have diagnostic and prognostic value for patients. The study of human genetics can be applied along the allelic spectrum, from rare variants in Mendelian disorders to common variants in polygenic traits and diseases. Here, I perform genetic studies along the allelic spectrum to uncover underlying biological and disease mechanisms for human growth and development. First, I demonstrated that exome sequencing can be a useful tool for diagnosing rare growth disorders and can lend unsuspected insights into the phenotypic spectrum associated with various genes. I also generated a novel resource for evaluating phase of rare variants, which will aid in the diagnosis of recessive Mendelian conditions. I next applied a segregation-based approach to identify mutations in ACAN as the genetic cause of a short stature syndrome, which generated insights into mechanisms of growth and skeletal maturation. I also applied a gene-based burden testing approach to try to find novel genes for a rare disorder of reproductive timing, and extended existing methods to leverage publicly available controls in a resource-efficient manner. As the gene-based burden testing approach has not been rigorously evaluated in the context of Mendelian disorders, I performed extensive simulations, which revealed components of genetic architecture that affect power of this approach. Finally, I performed genetic and functional studies at the HMGA2 locus to understand how common variants regulating HMGA2 influence height, a classic polygenic trait. These studies demonstrate how analyses of genetic variation along the allelic spectrum can offer complementary and unsuspected insights into biological processes and diseases. This dissertation covers a wide breadth of genetic studies and advances our understanding of the genetic architecture and pathophysiology of disorders of growth and development.Medical Science