PQG Seminar

Kari NorthProfessor of EpidemiologyCarolina Center for Genome Sciences, UNC Gillings School of Public HealthIntegrative Approaches to Identifying Function and Significance of Adiposity Susceptibility GenesIn 2019, ~100 million Americans were obese, fueling increases in obesity-related morbidity, mortality, and health care costs, largely from cardiometabolic diseases (CMD). GWAS have demonstrated the fundamental role of genetic susceptibility in obesity risk, including the >1000 loci identified to date. Each GWAS-identified locus potentially provides novel biologic insight; yet the identification of the functional variants, genes, and underlying pathways at these loci has limited translation for precision medicine. OMICs (e.g. genetics, transcriptOMICs, methylOMICs, and metabolOMICs) lie along pathways linking genetic susceptibility to obesity and are emerging as powerful disease biomarkers that provide targetable “mechanistic bridges” linking GWAS findings with obesity risk. OMIC scans in the same individuals in which obesity associated loci discoveries were made are now available, thereby facilitating comprehensive and efficient integration with genetic data to illuminate the underlying genes and mechanistic pathways of obesity-associated loci. Leveraging collaborations in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), TransOMICs for Precision Medicine (TOPMed) Program, and the Genome Sequencing Project (GSP), we have begun the process of identifying the genes underlying GWAS signals so that we can perform clinical characterization and conduct in vitro functional studies to characterize the molecular underpinnings and biological mechanisms of obesity-risk loci. Our approach will substantially move the field away from tag variants and loci to causal variants, genes, and mechanisms. We anticipate that this work will generate fundamental and important insights into the underlying etiology of obesity and ultimately point the way forward towards prevention and treatment.