Journal Article

Admixture-informed polygenic risk reporting using the ePRS framework

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

2026

Overview

Polygenic risk score values vary with genetic ancestry due to differences in population-specific allele frequencies and linkage disequilibrium patterns. We present a framework to calibrate polygenic risk scores based on ancestral makeup. We propose the “expected polygenic risk score” or ePRS, defined as the expected value of a polygenic risk score based on one’s global or local admixture patterns. We further define the “residual polygenic risk score” or rPRS as measuring the deviation of the polygenic risk score from the ePRS. The ePRS reflects the baseline ancestry-driven component of genetic risk, whereas the rPRS isolates an ancestry-agnostic measure of genetic liability. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the polygenic risk score-outcome association without further adjusting for principal components. Using the TOPMed and the All of Us datasets, effect size estimates for the rPRS (adjusted for ePRS) are similar to those obtained from polygenic risk scores adjusting for genetic principal components. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to interpret genetic risk across diverse populations. Polygenic risk scores vary with genetic ancestry. Here, the authors develop a framework to calibrate for genetic ancestry in these scores that leverages admixture analysis, separating out the ancestry-specific component of polygenic risk scores.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/43 / 631/1647/2217/457/649 / 631/208/212 / 631/208/729 / Association analysis / Binomial distribution / Computer Simulation / Decomposition / Estimates / Expected values / Gene Frequency / Genetic diversity / Genetic Predisposition to Disease / Genetic Risk Score / Genome-Wide Association Study / Genomes / Health risk assessment / Humanities and Social Sciences / Humans / Linkage Disequilibrium / Models, Genetic / multidisciplinary / Multifactorial Inheritance - genetics / Polymorphism, Single Nucleotide / Population genetics / Risk / Science / Science (multidisciplinary)