Abstract
Polygenic risk scores have the potential to improve health outcomes for a variety of complex diseases and are poised for clinical translation, driven by the low cost of genotyping (<$50 per person), the ability to predict genetic risk of many diseases with a single test, and the dramatically increasing scale and power of genetic studies that aid prediction accuracy. However, the major ethical and scientific challenge surrounding clinical implementation is the observation that they are currently of far greater predictive value in individuals of recent European ancestry than others. The better performance of such risk scores in European populations is an inescapable consequence of the heavily biased makeup of genome-wide association studies, with an estimated 79% of participants in all existing genetic studies being of European descent. Empirically, polygenic risk scores perform far better in European populations, with prediction accuracy reduced by approximately 2- to 5-fold in East Asian and African American populations, respectively. This highlights that—unlike specific clinical biomarkers and prescription drugs, which may individually work better in some populations but do not ubiquitously perform far better in European populations–clinical uses of prediction today would systematically afford greater improvement to European populations. Early diversifying efforts, however, show promise in levelling this vast imbalance, even when non-European sample sizes are considerably smaller than the best-powered studies to date. Polygenic risk scores provide a new opportunity to improve health outcomes for many diseases in all populations, but to realize this full potential equitably, we must prioritize greater inclusivity of diverse study participants in genetic studies and open access to resulting summary statistics to ensure that health disparities are not increased for those already most underserved.
