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Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal deformity that is associated with low bone mineral density (BMD). Vitamin D (Vit-D) supplementation has been suggested to improve BMD in AIS, and its outcomes may be related to genetic factors. The present study aimed to (a) investigate the synergistic effect between a low BMD-related gene (wingless-related integration site 16, <i>WNT16</i>) and two important Vit-D pathway genes (Vit-D receptor, <i>VDR,</i> and Vit-D binding protein, <i>VDBP</i>) on serum Vit-D and bone qualities in Chinese AIS patients and healthy adolescents, and (b) to further investigate the effect of ablating <i>Wnt16</i> on the cortical bone quality and whether diets with different dosages of Vit-D would further influence bone quality during the rapid growth phase in mice in the absence of <i>Wnt16</i>. A total of 519 girls (318 AIS vs. 201 controls) were recruited, and three selected single-nucleotide polymorphisms (SNPs) (<i>WNT16</i> rs3801387, <i>VDBP</i> rs2282679, and <i>VDR</i> rs2228570) were genotyped. The serum 25(OH)Vit-D level was significantly associated with <i>VDBP</i> rs2282679 alleles (OR = −4.844; 95% CI, −7.521 to −2.167, <i>p</i> < 0.001). Significant multi-locus models were identified by generalized multifactor dimensionality reduction (GMDR) analyses on the serum 25(OH)Vit-D level (<i>p</i> = 0.006) and trabecular area (<i>p</i> = 0.044). In the gene-edited animal study, <i>Wnt16</i> global knockout (KO) and wildtype (WT) male mice were provided with different Vit-D diets (control chow (1000 IU/Kg) vs. Vit-D-deficient chow (Nil in Vit-D) vs. high-dose Vit-D chow (20,000 IU/Kg)) from 4 weeks to 10 weeks old. <i>Wnt16</i> global KO mice had significantly lower serum 25(OH)Vit-D levels and higher liver <i>Vdbp</i> mRNA expression levels than WT mice. In addition, <i>Wnt16</i> global KO mice showed a decrease in bone density, cortical thickness and cortical area compared with WT mice. Interestingly, high-dose Vit-D chow led to lower bone density, cortical thickness, and cortical area in WT mice, which were less obvious in <i>Wnt16</i> global KO mice. In conclusion, <i>WNT16</i> may regulate the serum 25(OH)Vit-D level and bone qualities, which might be associated with <i>VDBP</i> expression. Further investigations with a larger sample size and wider spectrum of scoliosis severity are required to validate our findings regarding the interaction between <i>WNT16</i> and Vit-D status in patients with AIS.