Background & Rationale. Ageing is the strongest risk factor for cardiovascular disease, yet the molecular switches that couple ageing to cardiac dysfunction remain incompletely defined. CDON (a developmental signalling modulator with Hedgehog/Wnt crosstalk) is implicated in cardiogenesis. Our preliminary organoid work suggests that loss of CDON elevates Wnt activity and perturbs cardiac maturation. We aim to discover a CDON-linked ageing signature in population data and translate it into mechanistic tests in human cardiac organoids.
Research Questions.
Are CDON genomic variation and CDON-proximal molecular traits associated with biological ageing markers and cardiac outcomes?
Can we derive a composite CDON-Age Score that predicts cardiac ageing and disease risk beyond chronological age?
Are observed associations consistent with causal effects of CDON/Wnt signalling on cardiac traits?
Which modifiable pathways mediate these effects?
Objectives.
Map associations between CDON region variants, polygenic proxies for CDON expression, and ageing phenotypes (e.g., leukocyte telomere length, frailty indicators, blood biomarkers).
Test links with cardiovascular outcomes (HF, CAD, AF), imaging-derived phenotypes (cardiac MRI function/structure), and incident events.
Apply Mendelian randomization and colocalization to assess causality and pleiotropy.
Translate top biomarkers into perturbation readouts in hiPSC-derived cardiac organoids, modulating Wnt/Hedgehog activity to test directionality.