Allele frequency differences of causal variants have a major impact on low cross-ancestry portability of PRS

Genome-wide association studies (GWAS) are overwhelmingly biased toward European ancestries. Nearly all existing studies agree that transferring genetic predictions from European ancestries to other populations results in a substantial loss of accuracy. This is commonly referred to as low portability of polygenic risk scores (PRS) and is one of the most important barriers to the ethical clinical deployment of PRS. Yet, it remains unclear how much various genetic factors, such as linkage disequilibrium (LD) differences, allele frequency differences or causal effect differences, contribute to low PRS portability. In this study, we used gene expression levels in lymphoblastoid cell lines (LCLs) as a simplified model of complex traits with minimal environmental variation, in order to understand how much each genetic factor contributes to PRS portability from European to African populations. We found that cis- genetic effects on gene expression are highly similar between European and African individuals (![Graphic][1]). This stands in stark contrast to the very low estimates of cis -genetic correlation between Europeans and Africans in previous studies, which we demonstrate are artifacts of statistical bias. We showed that portability decreases with increasing LD differences in the cis -regions. We also found that allele frequency differences of causal variants have a striking impact on PRS portability. For example, PRS portability is reduced by more than 32% when the causal cis -variant is common (minor allele frequency, MAF > 5%) in European samples (training population) but is rarer (MAF < 5%) in African samples (prediction population). While large allele frequency differences can decrease PRS portability through increasing LD differences, we also show that causal allele frequency can significantly impact portability independently of LD. This observation suggests that improving statistical fine-mapping alone does not overcome the loss of portability caused by causal allele frequency differences. Lastly, we also found that causal allele frequency is the main genetic factor underlying differential gene expression levels across ancestries. We conclude that causal genetic effects are highly similar in Europeans and Africans, and low PRS portability is primarily due to allele frequency differences. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NIGMS ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The GEUVADIS dataset is available at https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-GEUV-4 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes https://github.com/XuanyaoLiuLab/AF\_PRS\_portability [1]: /embed/inline-graphic-1.gif