The illusion of polygenic disease risk prediction

A problem at the interface of genomic medicine and medical screening is that genetic associations of etiological significance are often interpreted as having predictive significance. Genome-wide association studies (GWAS) have identified many thousands of associations between common DNA variants and hundreds of diseases and benign traits. This knowledge has generated many publications with the understandable expectation that it can be used to derive polygenic risk scores for predicting disease to identify those at sufficiently high risk to benefit from preventive intervention. However, the expectation rests on the incorrect assumption that odds ratios derived from polygenic risk scores that are important etiologically are also directly useful in risk prediction and population screening.