Decoding causal genes and programs from regulatory variants in aortic valve disease

Briend, M.; Rufiange, A.; Duclos, V.; Mathieu, S.; Kanmacher, T.; Boudreau, D. K.; Gaudreault, N.; Saavedra-Armero, V.; Dagenais, F.; Couture, C.; Joubert, P.; Theriault, S.; Bosse, Y.; Mathieu, P.

doi:10.64898/2026.05.26.727981

bioRxiv · 10.64898/2026.05.26.727981

Decoding causal genes and programs from regulatory variants in aortic valve disease

Briend, M.·Rufiange, A.·Duclos, V.·Mathieu, S.·Kanmacher, T.·Boudreau, D. K.·Gaudreault, N.·Saavedra-Armero, V.·Dagenais, F.·Couture, C.·Joubert, P.·Theriault, S.·Bosse, Y.·Mathieu, P.

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Abstract

Aortic valve disease is common, yet its regulatory mechanisms remain poorly understood. We performed multi-omic profiling of human aortic valve interstitial cells (HAVICs), identifying 11,891 allele-specific chromatin accessibility QTLs (as-caQTLs), 48% novel to this cell type. These variants were enriched in active enhancers, disrupted transcription factor (TF) motifs, particularly AP-1, TEAD and GATA families, and were validated by allele-specific TF binding assays. A fine-tuned deep DNA sequence model prioritized common and rare variants at risk loci predicted to impact chromatin accessibility. Single-cell CRISPRi perturbation of 247 variants identified cis-target genes at 55 as-caQTL elements, including loci without eQTLs. We demonstrate that common regulatory variants controlling elastin and fibrillin impact the development of the aortic valve apparatus. We provide genetic evidence and a mechanistic framework for the contribution of a reduced aortic root size to CAVD risk. Perturbations identified core cell programs led by upstream regulators AHNAK, PDIA6, and RNFT1 converging on extracellular matrix production and iron transport.

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Briend, M., Rufiange, A., Duclos, V., Mathieu, S., Kanmacher, T., Boudreau, D. K., Gaudreault, N., Saavedra-Armero, V., Dagenais, F., Couture, C., Joubert, P., Theriault, S., Bosse, Y., Mathieu, P.. 2026-05-29. Decoding causal genes and programs from regulatory variants in aortic valve disease. https://doi.org/10.64898/2026.05.26.727981

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