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bioRxiv · 10.1101/2025.02.01.635985

A Litmus Test for Confounding in Polygenic Scores

Smith, S. P.·Smith, O. S.·Mostafavi, H.·Peng, D.·Berg, J. J.·Edge, M. D.·Harpak, A.
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Abstract

Polygenic scores (PGSs) are being rapidly adopted for trait prediction in the clinic and beyond. PGSs are often thought of as capturing the direct genetic effect of one's genotype on one's phenotype. However, because PGSs are constructed from population-level associations, they are influenced by factors other than direct genetic effects, including stratification, assortative mating, and dynastic effects ("SAD effects"). Our interpretation and application of PGSs may hinge on the relative influence of SAD effects, since they may often be environmentally or culturally mediated. We developed a method to measure these influences, Partitioning Genetic Scores Using Siblings (PGSUS, pron. "Pegasus"). PGSUS leverages a comparison of a PGS of interest based on a standard GWAS with a PGS based on a sibling GWAS--which is largely immune to SAD effects--to partition variance in a PGS (in a given sample) into components due to direct effects, SAD effects, and their covariance. Using PGSUS, we found that in many cases direct genetic effects contribute relatively little to PGS variation--most pronouncedly so in PGSs for social or behavioral traits, such as educational attainment or neuroticism. PGSUS further breaks down variance components by axes of genetic ancestry, allowing for a nuanced interpretation of SAD effects. In particular, PGSUS can detect stratification along major axes of ancestry as well as SAD variance that is "isotropic" with respect to axes of ancestry. Applying PGSUS, we found evidence of stratification in PGSs constructed using large meta-analyses of height as well as in multiple PGSs constructed using the UK Biobank. We show that a given PGS can suffer from stratification along a major axis of ancestry in one sample but not in another (for example, in comparisons of prediction in samples from contemporary vs. ancient DNA samples). We further show that when axes of stratification are shared between GWAS and prediction samples, stratification can both aid and impede phenotypic prediction accuracy. In summary, PGSUS offers advances in interpretation towards more informed application of polygenic scores.

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Smith, S. P., Smith, O. S., Mostafavi, H., Peng, D., Berg, J. J., Edge, M. D., Harpak, A.. 2025-02-04. A Litmus Test for Confounding in Polygenic Scores. https://doi.org/10.1101/2025.02.01.635985

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