Enhancing Polygenic Scores for Cardiometabolic Traits Through Tissue- and Cell Type-Specific Functional Annotations.

Abstract

Functional genomic annotations can improve polygenic scores (PGS) within and between genetic ancestry groups. While general annotations are commonly used in PGS development, tissue- and cell type-specific annotations derived from open chromatin and gene expression experiments may further enhance PGS for cardiometabolic traits. We developed PGS for 14 cardiometabolic traits in the UK Biobank using SBayesRC. We integrated GWAS summary statistics from FinnGen and GLGC with three annotation sources: i) baseline-LD model v2.2 (general annotations), ii) cell type-specific snATAC-seq peaks, and iii) tissue-specific eQTLs/sQTLs. We created PGS using two EUR LD reference panels (1.2M HapMap3 variants and 7M imputed variants). Tissue- and cell type-specific annotations showed stronger heritability enrichment than baseline-LD annotations on average, particularly coronary snATAC-seq peaks and fine-mapped eQTLs. Without annotations, HapMap3 and 7M variant PGS performed similarly. However, with all annotations, 7M variant PGS outperformed HapMap3 variant PGS (8% average increase in relative performance in EUR). Compared to using no annotations, modeling baseline-LD annotations improved performance by 5% for HapMap3 and 11% for 7M variant PGS, while modeling all annotations yielded improvements of 5% and 13%, respectively. Although annotations provided greater relative improvement for cross-ancestry prediction, they did not decrease the disparity in PGS performance between genetic ancestry groups. Functional annotations improved PGS for cardiometabolic traits. Despite strong heritability enrichment, tissue- and cell type-specific snATAC-seq and eQTL annotations provided marginal performance gains beyond general genomic annotations.