The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup

Author:

Huang Yu-JyunORCID,Kurniansyah Nuzulul,Goodman Matthew OORCID,Spitzer Brian W,Wang Jiongming,Stilp Adrienne,Laurie Cecelia,de Vries Paul S,Chen HanORCID,Min Yuan-I,Sims Mario,Peloso Gina M,Guo Xiuqing,Bis Joshua C,Brody Jennifer A,Raffield Laura MORCID,Smith Jennifer AORCID,Zhao Wei,Rotter Jerome I,Rich Stephen S,Redline Susan,Fornage MyriamORCID,Kaplan Robert,Franceschini Nora,Levy Daniel,Morrison Alanna C,Boerwinkle Eric,Smith Nicholas L,Kooperberg Charles,Psaty Bruce M,Zöllner Sebastian, ,Sofer TamarORCID

Abstract

AbstractPolygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called “expected PRS” (ePRS), the expected value of a PRS based on one’s global or local admixture patterns. We further define the “residual PRS” (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.

Publisher

Cold Spring Harbor Laboratory

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