Fig. 6. Genes and REs associated with PRS-like phenotypes are uniquely sensitized to SOX9 dosage.

a, ED₅₀ of SOX9-downregulated genes stratified by craniofacial disorder association. PRS-like associations as defined by Perrine et al. 2020 (ref. ⁴⁸). n of groups from left to right: 665, 13, 6, 8. b, Median dosage curves (based on both ED₅₀ and Hill exponent) of the same groups from a. c, Schematic of approach to conduct a multivariate GWAS on a PRS-defined endophenotype in healthy human individuals. d, Manhattan plot of PRS endophenotype GWAS. Red line indicates genome-wide significance. Candidate genes near top GWAS signals are labeled. e, ED₅₀ of REs stratified by linkage disequilibrium (LD, r² > 0.5) with any facial shape GWAS lead SNP (x axis, as defined in Naqvi, Hoskens et al. 2022 (ref. ²⁴) and further with any lead SNP associated with the PRS endophenotype GWAS from d (color). n of groups from left to right: 35,450, 209, 54. Points and error bars in a,e represent median and 95% confidence intervals as computed by 200 bootstraps (see Methods).