Is there a place for polygenic risk scores and gwas in modern genetic testing?

Abstract

Traditionally genetic testing has focused on rare high penetrance mutations such as BRCA1 mutations conferring risk of breast/ovarian cancer or MYOC mutations conferring risk of glaucoma. However, most Australians affected by common diseases such as these do not carry these mutations. Instead, most people are at high genetic risk due to the cumulative effect of many polygenes (that is, variants of individually small effect on risk). Recent genome-wide association studies have identified polygenes for virtually every complex human trait. There has been considerable recent excitement about polygenic risk scores (PRS) – these provide an index of genetic risk based on the cumulative effect of many polygenes. While there are now PRS for many diseases, their translational utility can be limited due to poor predictive performance or because of a lack of real world consequences. In my talk I will discuss applications of PRS across a range of traits including eye disease and cancer. In a general population setting I will show there are exciting opportunities for PRS to be used in improving risk stratification and screening. In the ‘high penetrance mutation’ setting, I will show that mutation penetrance can vary dramatically with PRS values, with important consequences for genetic testing.