目的：多组学联合分析揭示与非综合征型骨性III类错𬌗畸形遗传风险相关的细胞/时空表达异质性，阐明其内在分子遗传机制。

方法:通过两阶段病例-对照全基因组关联研究(genome-wide association study, GWAS)，识别与非综合征型骨性III类错𬌗畸形相关的易感位点/基因。运用全表型组关联研究(phenome-wide association analyses, PheWAS)分析相关遗传变异对多种疾病/性状的影响，整合基因型组织表达项目(Genotype-Tissue Expression, GTEx)数据进行全转录组关联研究(transcriptome-wide association studies, TWAS)揭示基因表达水平与疾病的关联。对细胞类型/时空表达中疾病易感基因的聚类进行量化，生成细胞/时空表达特异性的疾病评分，评估与疾病相关的跨物种细胞类型/时空表达的异质性。

结果：GWAS鉴定出多个与骨性III类错𬌗畸形相关的独立易感位点，PheWAS发现遗传变异与癫痫、体重等疾病/性状有影响。且骨性III类错𬌗畸形易感基因与人软骨膜间充质细胞、斑马鱼肢芽细胞和小鼠下颌骨与牙齿时空表达存在高度关联。通路富集分析结果显示，软骨膜间充质细胞可影响胚胎骨骼发育。拟时序分析揭示了软骨膜间充质细胞和骨祖细胞亚群之间的强相关性。

结论：本研究通过多组学联合分析，揭示了细胞/空间表达异质性在骨性III类错𬌗畸形疾病发展中的重要作用。

Objective: To further elucidate the intrinsic molecular genetic mechanisms of non-syndromic skeletal Class III malocclusion by revealing the cell type-/spatiotemporal-specific expression associated with genetic variants through combined multi-omics analyses.

Methods: Identification of susceptibility loci/genes associated with non-syndromic skeletal Class III malocclusion by a two-stage case-control genome-wide association study (GWAS). Phenome-wide association analyses (PheWAS) were applied to explore the possible effects of genetic variants associated with non-syndromic skeletal Class III malocclusion on multiple diseases/traits, and transcriptome-wide association studies (TWAS) integrating the Genotype-Tissue Expression (GTEx) project data reveal associations between gene expression levels and disease. The clustering of susceptibility genes in cell type-/spatiotemporal-specific expression was quantified across species, generating cell type-/spatiotemporal-specific expression disease scores for assessing disease-associated heterogeneity cross-species.

Results: The results of the study showed that GWAS meta-analyses identified nine independent susceptibility loci associated with skeletal Class III malocclusion. And genetic variants that had an impact on diseases/traits such as epilepsy and body weight. The susceptibility genes were significantly associated with human perichondrial mesenchymal stromal cells, zebrafish limb bud cell types, and mouse jaw and teeth spatiotemporal expression. Pathway enrichment analysis revealed that perichondrial mesenchymal stromal cells can influence signalling pathways in embryonic skeletal development. Pseudotemporal analysis revealed close relation between perichondrial mesenchymal stromal cells and osteoprogenitors.

Conclusions: This study reveals the important role of cell type-/spatiotemporal expression heterogeneity in the development of skeletal Class III malocclusion disease by combined multi-omics analysis.