Polygenic Risk for Morphogenetic Dysregulation and Bioelectrical Responses to Growth-Promoting and Growth-Inhibiting Cues in Young Donor-Derived Organoids

Background Aberrant reactions to growth-promoting and growth-inhibiting signals are consistently observed in tissues with poor regenerative capacity. While inherited variation contributes to such dysregulation, the extent to which polygenic liability alters cellular responses to pro-regenerative versus anti-regenerative stimuli remains unresolved. Methods Biospecimens from 879 young donors participating in a population cohort were reprogrammed into three-dimensional mesenchymal–epithelial organoids. Regenerative performance was quantified with a standardized morphogenesis index. Polygenic risk scores (PRSs) for morphogenetic dysregulation were derived for every donor. Using established voltage-sensitive dye imaging and family-wise error–controlled statistics, we assessed how organoid responses to fibroblast growth factor 2 (FGF2; growth-promoting) and transforming growth factor-β (TGF-β; growth-inhibiting) related to morphogenesis indices and PRSs via linear regression in the full sample and within male and female subgroups, adjusting for age, sex (in the full model), ancestry, and alcohol-use severity. Results Elevated PRSs were associated with broad attenuation of stimulus-evoked membrane depolarization across anterior ectodermal, lateral mesodermal, and posterior endodermal territories during exposure to both growth-promoting and growth-inhibiting factors. Notably, a discrete posterior organizer–like domain displayed PRS-linked hyperpolarization exclusively under growth-inhibiting conditions. Sex-stratified analyses revealed convergent as well as sex-specific bioelectrical signatures of PRS-sensitive signaling. Conclusions Inherited polygenic liability for morphogenetic dysregulation modulates tissue-level bioelectrical dynamics in response to opposing regenerative cues, offering genetically informed biomarkers for regenerative health assessment.