Associations between brain phenotypes and temporomandibular disorders: An integrative multi-omics investigation.

OBJECTIVE: We proposed that overlooked neuropathological mechanisms involving brain phenotypes play a critical role in the pathogenesis of temporomandibular disorders (TMD). METHODS: We employed an integrative multi-omics approach combining bidirectional Mendelian randomization (MR) - a genetic method to infer causal relationships - applied to 3,935 brain imaging-derived phenotypes, transcriptomic analysis (examining gene activity) of a TMD rodent model, and cell-type-specific MR using single-cell expression quantitative trait loci. RESULTS: Bidirectional MR identified 85 putatively causal brain phenotypes for TMD, predominantly white matter tracts (50/85). Transcriptomics yielded 197 medullary and 22 trigeminal differentially expressed genes. Cell-type MR implicated C1S in excitatory neurons and ARHGAP45 in microglia as risk genes. CONCLUSION: This study supports the role of brain phenotypes in TMD neuropathology, suggesting a neural (medulla-trigeminal) pathway, and provides preliminary evidence for potential biomarkers and therapeutic targets.