Single-cell multiomic QTL mapping reveals state-dependent genetic regulation and associated gene during cellular senescence
- 1Department of Bioinformatics, State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medica
Abstract
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.
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BibTeX
@misc{yi2026singlecell,
title = {{Single-cell multiomic QTL mapping reveals state-dependent genetic regulation and associated gene during cellular senescence}},
author = {X. Yi and X. Wang and K. Liu and L. Zhao and F. Chen and Q. Jian and J. Wang and H. Lu and W. Dong and Y. Zhou and Y. Chang and X. Gu and P. C. Sham and D. Huang and M. J. Li},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752532},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752532v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Single-cell multiomic QTL mapping reveals state-dependent genetic regulation and associated gene during cellular senescence
AU - X. Yi
AU - X. Wang
AU - K. Liu
AU - L. Zhao
AU - F. Chen
AU - Q. Jian
AU - J. Wang
AU - H. Lu
AU - W. Dong
AU - Y. Zhou
AU - Y. Chang
AU - X. Gu
AU - P. C. Sham
AU - D. Huang
AU - M. J. Li
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752532
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752532v1
AB - 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.
ER -