Grant: Operating Grant - PA: Genetics (Bridge Funding: Research Priorities)

Common inherited diseases, including heart disease and autoimmunity, are caused by many mutations that occur throughout the genome. These mutations often lie in the parts of the genome adjacent to the genes themselves, and control when and where genes are expressed. For instance, a mutation can cause the gene to turn on or off at the wrong time or in the wrong cell. Our study focuses on Atrial fibrillation (AF), a common heritable form of arrhythmia. Although we suspect that most AF-associated mutations act by changing gene expression, the molecular mechanisms by which they do so remain incompletely understood. Further, it is unclear whether the many mutations across the genome that impact AF converge on common cellular processes. Our goal is to determine which AF-associated mutations modulate gene expression, how they do so, and how a patient's genetics influences the core cellular processes of heart cells. We will experimentally test how each mutation alters gene expression in a synthetic system using healthy heart cells. Next, we will measure the genes expressed in the cells of AF patients to find groups of genes that work together in disease-related processes. Finally, we will determine how a patient's genetics influences the ways in which heart cells interpret expression-altering mutations. This project will improve our understanding of the molecular biology underlying AF, essential to designing new AF diagnostics and treatments, and, more generally, our understanding of common inherited disease genetics.