How cellular senescence reshapes inherited regulatory effects across chromatin and transcription, and eventually contribute to non-coding risk loci of complex diseases, remains elusive. We generated single-cell multiome ATAC-RNA profiles from proliferating and replicatively senescent primary HUVECs derived from 100 genotyped donors. Alongside state-resolved eQTL and caQTL mapping, we implemented covariance-aware multivariate QTL mapping to identify chromatin accessibility-expression QTLs (caeQTLs), modeling accessibility and expression as a joint phenotype. Joint analysis recovered moderate, asymmetric and modality-distributed associations missed by single-modality scans, revealed senescence-associated regulatory programs, and prioritized candidate causal variants and effector genes at cardiovascular loci. Fine-mapping, chromatin-state annotation and heritability enrichment, together with independent SNP-to-gene algorithms, provided convergent orthogonal support. Mechanistic dissection revealed that rs2019090 modulates PDGFD expression and endothelial phenotypes through senescence-amplified, allele-specific, HMGA1-associated enhancer-promoter regulation. This study establishes senescence-resolved joint multiomic QTL mapping as a framework for narrowing the missing regulation gap in complex disease genetics.
Yi, X., Wang, X., Liu, K., Zhao, L., Chen, F., Jian, Q., Wang, J., Lu, H., Dong, W., Zhou, Y., Chang, Y., Gu, X., Sham, P. C., Huang, D., Li, M. J.
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