Genetic evidence linking ankylosing spondylitis to temporomandibular disorders: a bidirectional Mendelian randomization study

Temporomandibular disorders (TMD) are complex musculoskeletal conditions affecting the temporomandibular joint, with potential connections to immune-mediated inflammatory diseases (IMIDs). This study aimed to investigate the genetic causal relationships between representative IMIDs and TMD using bidirectional Mendelian randomization (MR) analysis, coupled with tissue-specific gene expression. A two-sample MR design was employed using genome-wide association study summary statistics from European populations. Four IMIDs were examined: Systemic Lupus Erythematosus (SLE), Ankylosing Spondylitis (AS), Psoriasis (PSO), and Inflammatory Bowel Disease (IBD). Multiple statistical methods, including inverse variance weighted (IVW), weighted median, and MR-Egger regression, were used to assess potential causal associations. Sensitivity analyses were conducted to evaluate heterogeneity, pleiotropy, and robustness of findings. Tissue-specific expression patterns of MR-identified genes were analyzed using GTEx data. AS showed a significant causal effect on TMD (OR = 1.037, 95% CI: 1.022–1.053, p < 1.045e-06). No causal effects were found for SLE (OR = 0.997, p = 0.697), PSO (OR = 1.021, p = 0.365), or IBD (OR = 0.959, p = 0.678). Reverse MR indicated no TMD effect on IMIDs. Tissue-specific expression analysis highlighted broad expression of ERAP1 across tissues, whereas GRM4 showed neural-specific high expression. Mendelian randomization supports a genetic causal effect of AS on TMD. This effect may involve AS-related inflammatory pathways (e.g., ERAP1) and/or GRM4-mediated neural signaling in the anterior cingulate cortex.