Causal association of immune-related genes with mouth ulcers: findings from summary-based Mendelian randomization and transcriptome-wide association analysis

Oral ulceration is the most common ulcerative condition in humans, yet its underlying etiology remains poorly understood. To identify potential causal genes involved in the pathogenesis of mouth ulcers, we applied summary data-based Mendelian randomization (SMR) using eQTL data from GTEx and CAGE, along with a transcriptome-wide association study (TWAS). The SMR analysis of GTEx data identified 41 significant probes, with <i>LRRC37A4P</i>, <i>RP11-707O23.5</i>, and <i>RP11-259G18.3</i> standing out. In parallel, the CAGE SMR identified 67 probes corresponding to 58 genes, including <i>CCR2</i>, <i>MGC57346</i>, and <i>C17orf69</i>. TWAS further identified 181 significant genes, with 37 overlapping with GTEx SMR findings and 27 with CAGE SMR findings. Functional enrichment analysis revealed a strong involvement of immune-related pathways, especially those involving <i>HLA-DRB1</i> and <i>CCR2</i>. Differential expression analysis reinforced the relevance of <i>IL12RB1</i> and <i>HLA-DRB1</i>, which were consistently significant across both SMR and TWAS analyses. Collectively, these findings underscore the importance of immune-regulatory genes, particularly members of the CCR gene family and the HLA complex, in the genetic architecture of mouth ulcers. This integrative approach provides insights into potential therapeutic targets and advances our understanding of the genetic basis underlying this prevalent condition.