Genetic Association Analysis Between Depression and Gastroesophageal Reflux Disease- Related Phenotypes

Abstract Objective A plethora of studies have illuminated the significant association between depression and Gastroesophageal Reflux Disease (GERD), especially refractory gastroesophageal reflux disease (rGERD), yet the causal interplay and directionality of this relationship remain largely unexplored. This study aims to shed light on the bidirectional causative connections and the potential genetic mechanisms underlying the relationship between depression and GERD, as well as its subtypes. Methods Utilizing comprehensive summary data from Genome-Wide Association Studies (GWAS) pertaining to depression, GERD, Reflux Esophagitis (RE), and Non-Erosive Reflux Disease (NERD), this study implemented Mendelian Randomization to discern the independent causal relationships between depression and these gastroesophageal disorders. We employed an integrative approach, amalgamating data from GWAS, Expression Quantitative Trait Loci (eQTL), and other multi-omics analyses. Techniques such as SMR and FUMA were applied to identify potential pathogenic genes implicated in depression and the subtypes of GERD. Enrichment analyses were conducted to elucidate the potential biological pathways through which depression modulates GERD and its variants. Results The study revealed that depression significantly increases the risk of developing GERD and NERD, but not RE. No causal link was identified between GERD, RE, NERD, and depression. In-depth analysis through SMR and FUMA pinpointed GMPPB as a potential susceptibility gene for depression, manifesting across the brain, spinal cord, and peripheral blood. For GERD, the identified susceptibility genes present in the gastroesophageal junction, esophageal mucosal and muscular layers, and peripheral blood included RP4-717I23.3, RAB7L1, BROX, TAF1B, RP11-95D17.1. For NERD, potential susceptibility genes localized in similar tissues comprised GBP3, METTL18, SERPINC1, ZNF496, AC016683.6, PAX8GLS, LARS2, NCKIPSD, QRICH1, AMT. The genetic loci linked to both depression and GERD predominantly cluster in areas such as the T cell receptor signaling pathway, DNA binding transcription factor activity, sequence-specific DNA binding, Rickman tumor differentiated well vs moderately DN, etc. Genetic loci associated with depression and NERD are mainly concentrated in areas of Nucleosome organization, Protein and complex subunit organization, and, similarly, the T cell receptor signaling, etc. Conclusion The findings of this study indicate that depression contributes to an increased incidence of GERD and NERD. The potential mechanisms underpinning this association might involve the brain-gut axis, encompassing neuroimmune pathways, DNA and RNA transcriptional regulation, and protein metabolism processes.