Polygenic Disease and PGT-P - Ethics and Efficacy in Prediction of Disease

Abstract

Pre-implantation genetic testing (PGT) began as a method to reduce risk for monogenic disease with known parental risk. PGT-P depends on the accuracy of the polygenic risk scoring (PRS). And susceptibility to a complex disease is multi-factorial. The genetic component is complex and these genetic variants each have a small effect throughout the genome. Environmental factors, as well as rare genetic variations of large effect, play a notable role. Even with more common disorders and large GWAS cohorts, clinical medicine has raised concerns about the predictability, and more importantly, generalizability, of these data. Limited clinical utility has been identified in applying PRS to clinical care except for increased implementation of screening. And positive implications will be harder to document when the diagnostic (in the embryo) is so remote from the actual disease development with many opportunities for environmental influence over the course of a lifetime. Additionally, when selected due to familial risk, the common variants may have limited implication for disease risk in the offspring from the same couple where potential rare genetic variation accounts for a substantial degree of within family risk. Lastly, there are new ethical concerns. For instance, how does application of PGT-P increase social inequity - given both the financial cost of the procedure (which may now require many more cycles to get a “desired” embryo) and the largely Northern European databases utilized for the defining GWAS studies? Will such diagnostics diminish efforts to improve the lives of those remaining in society who are affected? Will lessening the chance for one disorder increase risk for another? And without better understanding of the environmental and epigenetic components, calculating an absolute risk reduction becomes much more difficult so how do you appropriately consent for this procedure. This is particularly true when selecting against several disorders/diseases in the single embryo.