Integrative Genomic and Epigenomic Dissection of Facial Morphology in Chinese Populations

Facial morphology is a highly heritable human trait, yet its underlying genetic architecture remains largely unresolved despite recent progress from genome-wide association studies (GWAS). Here, we integrated univariate and multivariate analyses of 230 facial phenotypes with GWAS and epigenome-wide association studies to identify genomic and epigenomic markers influencing facial variation in Chinese populations. Univariate analyses identified 144 single nucleotide polymorphisms (SNPs) and 34 CpG methylation sites, whereas multivariate canonical correlation analyses detected an additional 80 SNPs and 734 CpG sites across four key facial regions (eyebrow-eye complex, nose, mouth, and facial contour), with 50 SNPs overlapping those from the univariate analysis. In total, 174 SNPs and 768 CpG sites were associated with facial morphology, with 70.1% of SNPs and 57.5% of CpG sites linked methylation quantitative trait loci validated in a replication cohort. Functional mapping and annotation of GWAS prioritized 42 lead SNPs near genes such as SOX9, VPS13B, GAB2, and DOCK9, emphasizing their roles in craniofacial development. Notably, CpG sites accounted for more phenotypic variance in facial morphology (mean 8.83%, max 13.68%) than SNPs alone (mean 2.85%, max 6.63%). Integrating both genomic and epigenomic markers further enhanced the explainable variance (mean 9.85%, max 16.57%). This study represents the first comprehensive analysis of both genomic and epigenomic influence on facial morphology in Chinese populations. Our findings demonstrate that CpG methylation, alongside SNPs, contributes substantially to facial variation, explaining an even greater proportion of morphological variance and underscoring the importance of epigenetic regulation in shaping facial morphology.