Grant: Fellowship - Priority Announcement: Circulatory and Respiratory Health

Aortic stenosis (AS) is the leading cause of heart valve disease in the developed world. Apart from replacement of the aortic valve, there is currently no treatment for this disease. Over the last decade, more than a dozen genetic changes that contribute to AS have been identified. However, this variation is common and has only a small effect. Rarer variants that change the sequence of proteins may have stronger effects, so identifying these variants could highlight new genes that contribute to AS. By using whole-exome sequencing data (i.e., the data pertaining to all the sequences that encode the series of amino acids that compose proteins) from the UK Biobank, a large longitudinal study in the United Kingdom, I will compare the frequency of protein-coding variants between individuals with AS and those without. I expect to identify, for the first time, rare protein-coding variants that implicate novel molecular pathways that contribute to the development of AS. In the last two decades, the use of founder populations, which are populations that are derived from a small number of ancestors due to a founder effect, led to the identification of many variants associated with multiple diseases, including cardiovascular diseases. Quebec is a well-studied founder population. Therefore, to identify genetic variants associated with AS, in addition to the UK Biobank, I will use whole-exome sequencing data from two Quebec cohorts: Translational-Omics in Aortic Stenosis (TOmAS) and CARTaGENE. TOmAS is a clinical study of AS led by Dr. George Thanassoulis at the MUHC, while CARTaGENE is an ongoing, long-term, population-based health study on 43,000 people from the province of Quebec. The use of the Quebec Founder Population will also allow us to identify genetic contributions to AS that are different between Quebecers and other populations of European descent.