In a polygenic disorder, a single variant is not informative for assessing disease risk. Instead, a genetic loading conferred by the combined set of risk variants is necessary to obtain a measure that has sufficient information to identify those at high risk. There are many possible approaches to combine information across loci; the genetic risk is most often assessed through the polygenic risk score (PRS), a weighted sum of the number of risk alleles an individual carries. Despite methodological concerns about construct, content, and criterion validity of PRS [1], many studies have shown that PRSs can predict disease status in research-based case-control studies [2–4]. More convincingly, the prediction is also valid in population-based cohort studies and in electronic health record-based studies [5–7].
