Clinical use of current polygenic risk scores may exacerbate health disparities

Abstract

Polygenic risk scores (PRS) are poised to improve biomedical outcomes via precision medicine. However, the major ethical and scientific challenge surrounding clinical implementation is that they are many-fold more accurate in European ancestry individuals than others. This disparity is an inescapable consequence of Eurocentric genome-wide association study biases. This highlights that-unlike 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 PRS today would systematically afford greater improvement to European descent populations. Early diversifying efforts show promise in levelling this vast imbalance, even when non-European sample sizes are considerably smaller than the largest studies to date. To realize the full and equitable potential of PRS, we must prioritize greater diversity in genetic studies and public dissemination of summary statistics to ensure that health disparities are not increased for those already most underserved.

The genetics of human hematopoiesis and its disruption in disease

“…One important goal over the next 10 years is to map the full allelic spectrum of how genetic variation regulates hematopoiesis in health and disease. Furthermore, despite the enormous strides the field of genetics has already made, and a critical shortcoming has been that the majority of large studies have been confined to populations of European ancestry (Martin et al , ). Therefore, an essential part of this challenge is to expand genetic studies to populations of different ancestries.…”

Predicting venous thromboembolism risk from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges

“…The AUC achieved by this method in African Americans exceeds the reported AUC in the original study population (0.677), and greatly exceeds the expected theoretical maximum AUC that can be achieved for predicting complex phenotypes from coding variants alone. This is particularly interesting because previous work has shown that genetic risk models developed in European perform on average 25% as well in African populations as they do in European populations (Martin et al, ). This suggests that the method proposed by Soria et al may be clinically useful in predicting VTE in African Americans, but would need to be evaluated in a larger cohort.…”

“…Within each group scores are sorted by AUC. Accuracy, sensitivity, specificity, and F1 are calculated using a cutoff of 0.5 for all predictions (Martin et al, 2019).…”

Advances in genetics toward identifying pathogenic cell states of rheumatoid arthritis

“…In clinical practice, RA can be detected by the presence of a few biomarkers, such as RF, autoantibodies, and ACPA. However, preventative measures to assess the risk of onset of RA, before detection of these biomarkers, is falling behind successful predictive clinical models of breast cancer, heart disease, and type 1 diabetes . It is imperative that genetic findings in the field of RA be used to improve risk models so that at‐risk individuals can benefit from early treatment and prevention.…”

“…However, preventative measures to assess the risk of onset of RA, before detection of these biomarkers, is falling behind successful predictive clinical models of breast cancer, heart disease, and type 1 diabetes. 79 It is imperative that genetic findings in the field of RA be used to improve risk models so that at-risk individuals can benefit from early treatment and prevention. Therefore, future efforts for identifying therapeutic targets, running RA clinical trials, and developing clinical models must heavily encourage the participation of genetically diverse individuals.…”