How to assemble the cardiovascular system: instructions from the genome

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Cardiovascular disease is the leading cause of death worldwide. Inherited DNA sequence variants play a role in conferring risk for disease. Our knowledge of the genetic loci associated with risk of cardiovascular disease in humans has been greatly expanded by recent technological advancements. However, only a fraction of the genetic risk factors have been identified and characterized so far. A major problem is that only a small fraction of the genome, the one occupied by protein-coding genes, is understood in terms of its function. Therefore, we can only predict the harmful effects of genetic variations occurring within this fraction. However, the vast majority of sequence variants associated to disease reside elsewhere in the genome. Thus, it is crucial that the non-coding functional genome (regulatory genome) be discovered and characterized. This project will use state-of-the-art technologies to identify the functional, non-coding human genome that controls formation of the outflow tract of the heart and the great vessels. We will then link the identified human regulatory information to known genetic variations associated to cardiovascular disease risk, and to available data from our collaborators on congenital heart disease (CHD). Our results will be stored into a searchable, open-access web application to facilitate their clinical translation. We expect that the results of this project will lead to the discovery of genetic variants associated to congenital heart disease and clinical phenotypes disease risk, and will eventually expand diagnostic and therapeutic capacities.