Can polygenic risk scores help explain disease prevalence differences around the world? A worldwide investigation

Complex disorders are caused by a combination of genetic, environmental and lifestyle factors, and their prevalence can vary greatly across diferent populations. The extent to which genetic risk, as identifed by Genome Wide Association Study (GWAS), correlates to disease prevalence in diferent populations has not been investigated systematically. Here, we studied 14 diferent complex disorders and explored whether polygenic risk scores (PRS) based on current GWAS correlate to disease prevalence within Europe and around the world. A clear variation in GWASbased genetic risk was observed based on ancestry and we identifed populations that have a higher genetic liability for developing certain disorders. We found that for four out of the 14 studied disorders, PRS signifcantly correlates to disease prevalence within Europe. We also found signifcant correlations between worldwide disease prevalence and PRS for eight of the studied disorders with Multiple Sclerosis genetic risk having the highest correlation to disease prevalence. Based on current GWAS results, the across population diferences in genetic risk for certain disorders can potentially be used to understand diferences in disease prevalence and identify populations with the highest genetic liability. The study highlights both the limitations of PRS based on current GWAS but also the fact that in some cases, PRS may already have high predictive power. This could be due to the genetic architecture of specifc disorders or increased GWAS power in some cases.