Partitioning genetic pleiotropy within tissue-specific regulatory patterns

GWAS-associated variants of related complex traits indicate the presence of pleiotropic clusters often related to tissue-specific epigenomic profiles. The authors introduce J-PEP, a novel framework that enables tissue-aware interpretation of complex trait genetic architecture and PEPA, a cross-modal validation metric. J-PEP factorizes trait and tissue data matrices jointly to identify soft clusters of SNPs that capture both pleiotropic and shared epigenomic patterns in tissues, improving both clustering efficiency and mechanistic interpretation.