Portability of 245 Polygenic Scores when Derived from the UK Biobank and Applied to 9 Ancestry Groups from the Same Cohort

(The American Journal of Human Genetics 109, 12–23; January 6, 2022) An unfortunate corruption of two equations on page 14 appeared in the version of this paper published on January 6. It has been corrected here and online. The publisher apologizes for this error. New formula used in LDpred2 We also slightly modify the formula used in Privé et al.;32 we have previously usedseγˆj2=y˘−γˆjG˘jTy˘−γˆjG˘jn−K−1G˘jTG˘j≈y˘Ty˘nG˘jTG˘j≈varynvarGj,where γˆj is the marginal effect of variant j, and where y˘ and G˘j are the vectors of phenotypes and genotypes for variant j residualized from K covariates, e.g., centering them. The first approximation expects γˆj to be small, while the second approximation assumes the effects from covariates are small. However, we have found here that some variants can have very large effects, e.g., one variant explains about 30% of the variance in bilirubin log-concentration. Then, instead we compute(y˘−γˆjG˘j)T(y˘−γˆjG˘j)=y˘Ty˘−2γˆjG˘jTy˘+γˆj2G˘jTG˘j=y˘Ty˘−γˆj2G˘jTG˘j,which now gives(n−K−1)se(γˆj)2=y˘Ty˘−γˆj2G˘jTG˘jG˘jTG˘j=y˘Ty˘G˘jTG˘j−γˆj2≈var(y˘)var(Gj)−γˆj2,finally giving (note the added term γˆj2)sdGj≈sdy˘nseγˆj2+γˆj2.(Equation 1) Figure S23 shows that the updated formula Equation 1 is better; we now use it in the code of LDpred2, and also recommend using it for the QC procedure proposed in Privé et al.32 Portability of 245 polygenic scores when derived from the UK Biobank and applied to 9 ancestry groups from the same cohortPrivé et al.The American Journal of Human GeneticsJanuary 06, 2022In BriefThe low portability of polygenic scores (PGSs) across global populations is a major concern that must be addressed before PGSs can be used for everyone in the clinic. Indeed, prediction accuracy has been shown to decay as a function of the genetic distance between the training and test cohorts. However, such cohorts differ not only in their genetic distance but also in their geographical distance and their data collection and assaying, conflating multiple factors. In this study, we examine the extent to which PGSs are transferable between ancestries by deriving polygenic scores for 245 curated traits from the UK Biobank data and applying them in nine ancestry groups from the same cohort. Full-Text PDF