Exploratory Analysis of Ancestry‐Informed Polygenic Risk Scores in Korean Patients With Mature B‐Cell Neoplasms

Abstract

ABSTRACT Background Polygenic risk scores (PRS) capture cumulative germline susceptibility and have demonstrated clinical relevance in multiple complex diseases. However, data on PRS performance in mature B‐cell neoplasms remain limited, particularly in East Asian populations. Methods We analyzed 246 Korean patients with mature B‐cell neoplasms and related plasma‐cell disorders. GWAS‐derived susceptibility variants were filtered for genome‐wide significance and pruned for linkage disequilibrium using the 1000 Genomes East Asian (EAS) reference population, followed by cross‐dataset genotype harmonization. A 37‐SNP cross‐entity score was constructed together with phenotype‐matched PRS for multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and diffuse large B‐cell lymphoma (DLBCL). Results The overall 37‐SNP score was modestly but significantly higher in cases than in the 1000 Genomes EAS reference population (p = 0.024; OR per 1‐SD, 1.19; 95% CI, 1.02–1.38). A more distinct association emerged for MM: the MM‐specific PRS was associated with higher odds of disease (OR per 1‐SD, 1.386; 95% CI, 1.149–1.672; p = 0.000642), whereas CLL and DLBCL were not significant. Although discrimination remained modest (AUC, 0.594 for MM), MM cases were enriched above the EAS 95th percentile (OR, 2.21; p = 0.026), and rs7193541 and rs6599175 remained significant after false‐discovery‐rate correction. Conclusions Ancestry‐informed PRS identified a detectable polygenic component in Korean patients with mature B‐cell malignancies and related plasma‐cell disorders, with the most consistent evidence observed for MM. These findings support further evaluation of disease‐specific, ancestry‐informed PRS approaches rather than broadly aggregated susceptibility models.