Dissecting the Genetic Architecture of Human Phenotypes through Pleiotropic Enhancers

Studies dissecting the genetic architecture of human phenotypes and disease point to genetic variation in the noncoding region of the genome, particularly within enhancers. Enhancers have traditionally been believed to exert their regulatory effects on their target genes in a cell type-specific and time-specific manner. However, emerging evidence suggests that enhancers can be pleiotropic, where they can exert their effects across multiple tissue types and influence multiple phenotypes. This raises the possibility that enhancer pleiotropy may be a fundamental component of the genetic architecture of human phenotypes, warranting further investigation since enhancer function is typically studied in a cell-type specific manner. In this dissertation, I assess the role of enhancer pleiotropy in human phenotypes and disease and demonstrate that enhancer pleiotropy contributes to the genetic architecture of human phenotypes. First, I investigate the role of enhancer pleiotropy in human adaptation, specifically Tibetan adaptation to high altitude. I expand on the pleiotropic role of a known pleiotropic enhancer under strong selection in Tibetans, showing that it regulates thermogenic activity in adipocytes in response to hypoxia and thermogenic stimulation independently. This finding suggests that the enhancer is involved in regulating thermogenic activity in Tibetans in response to cold temperatures experienced in the Tibetan Plateau. Second, I investigated the role of enhancer pleiotropy in human disease, specifically obesity and cardiometabolic disease (CMD). I functionally dissected enhancer variants associated with high adiposity but opposite CMD-risk profiles. I identified the likely target genes of these enhancers and perturbed the genes in adipocytes, discovering that many of these genes impact fat accumulation and molecular pathways associated with CMD risk, such as angiogenesis, cholesterol efflux, and insulin signaling. These findings indicate that enhancer variants associated with adiposity but opposite CMD-risk regulate genes with pleiotropic effects in adipocytes. Collectively, the work I present in this dissertation demonstrates that enhancers can confer pleiotropic effects, underscoring the need to study enhancer pleiotropy in future work dissecting the genetic architecture of human phenotypes.