Association of PTH1R Gene Polymorphisms with Three-Dimensional Mandibular Morphology Across Three Recruitment Cohorts

Parathyroid hormone 1 receptor (PTH1R) regulates chondrocyte differentiation and mandibular condylar cartilage development, but its contribution to adult mandibular morphology remains unclear. We investigated associations of two PTH1R single-nucleotide polymorphisms (SNPs), rs724448 and rs2242116, with three-dimensional mandibular morphology in 448 orthodontic patients recruited in Japan (199), Korea (79), and Egypt (170). Salivary DNA was genotyped, and computed tomography images were analyzed using geometric morphometrics and conventional measurements. Multivariate Procrustes analysis evaluated overall mandibular shape. Cohort-specific regressions examined natural-log-transformed centroid size (ln(centroid size)), principal component scores, and conventional measurements, adjusting for sex and age and additionally for imaging modality in Japan. Estimates were combined using inverse-variance fixed-effect meta-analysis. Neither variant showed a significant whole-shape association after correction for two SNP tests. Secondary analyses yielded negative estimates for ln(centroid size) and nominal associations with selected anteroposterior dimensions and cohort-specific principal component scores. None remained significant after either Bonferroni or Benjamini-Hochberg false-discovery-rate correction across 408 tests. These findings provide no statistically robust evidence linking either variant to adult mandibular morphology. Nominal findings require independent replication.