Abstracts from the 55th European Society of Human Genetics (ESHG) Conference: e-Posters

Abstract

Background/Objectives: With the increasing availability of biobank-scale datasets that incorporate both genomic data and electronic health records, many associations between genetic variants and phenotypes of interest have been discovered. Polygenic risk scores (PRS), which are being widely explored in precision medicine, use the results of association studies to predict the genetic component of disease risk by accumulating risk alleles weighted by their effect sizes. However, limited studies have thoroughly investigated best practices for PRS in global populations across different diseases. Methods: In this study, we utilize data from the Global-Biobank Meta-analysis Initiative (GBMI, N = 2.1 million), which consists of individuals from diverse ancestries and across continents, to explore methodological considerations and PRS prediction performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRS using classic P+T and Bayesian (PRSCS) methods. Results: We found that the genetic architecture, such as SNPbased heritability and polygenicity, varied greatly among endpoints. For both PRS construction methods, using a European ancestry LD reference panel resulted in comparable or higher prediction accuracy compared to several other non-European based panels; this is largely attributable to European descent populations still comprising the majority of GBMI participants. PRS-CS overall outperformed P+T, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma which has known variation in disease prevalence across global populations. Conclusion: Overall, we provide lessons for PRS construction, evaluation, and interpretation using the GBMI and highlight the importance of best practices for PRS in the biobank-scale genomics era.