Objective: A number of studies have shown that there is a significant correlation between depression and gastroesophageal reflux disease (GERD), but the causal relationship between the two and the direction of correlation are not clear. This paper aims to explore the bidirectional causal inference between depression and GERD and its subtypes and the underlying mechanism of the disease from the genetic level. Methods: Based on the aggregated data of the genome-wide association study (GWAS) of depression, GERD, reflux esophagitis (RE) and non-erosive gastroesophageal reflux disease (NERD), Mendelian randomization was used to explore the independent causal relationship between depression and GERD, RE and NERD. Multiple omics data such as GWAS and eQTL were integrated to explore the potential pathogenic genes of depression, GERD and its subtypes by SMR and FUMA methods, and the potential mechanism of depression affecting GERD and its subtypes was evaluated by enrichment analysis. Results: Depression increased the risk of GERD and NERD, but not RE. GERD, RE, and NERD do not increase the risk of depression. Through SMR and FUMA analysis, the potential susceptibility genes for depression were identified as GMPPB, and the potential susceptibility genes for GERD were identified as RP4-717I23.3, RAB7L1, BROX, TAF1B, RP11-95D17.1. The NERD potential susceptibility genes were GBP3, METTL18, SERPINC1, ZNF496, AC016683.6, PAX8GLS, LARS2, NCKIPSD, QRICH1 and AMT. Depression and GERD gene loci are mainly concentrated in T cell receptor signaling pathway, DNA-binding transcription factor activity, RNA polymerase II transcriptional regulation region sequence-specific DNA binding. The depression and NERD gene loci are mainly concentrated in nucleosome assembly, protein and complex subunit assembly, and T cell receptor signaling pathway. Conclusion: Depression can increase the risk of GERD and NERD, and the underlying mechanism may play a role through brain-gut axis, neuroimmune pathway, DNA and RNA transcription and regulation, protein metabolism, etc.