OBSERVATIONAL, CAUSAL RELATIONSHIP AND SHARED GENETIC BASIS BETWEEN CHOLELITHIASIS AND GASTROESOPHAGEAL REFLUX DISEASE: EVIDENCE FROM A COHORT STUDY AND COMPREHENSIVE GENETIC ANALYSIS

Background
Cholelithiasis and gastroesophageal reflux disease (GERD) contributed to significant health concern. Research on the relationship between cholelithiasis and GERD is scarce, with inconsistent and insufficient findings. Besides, the causality and underlying biological connections remain unclear. In this study, we comprehensively investigate the potential observational, causal and genetic relationships between cholelithiasis and GERD with observational and genetic-level approaches.
Methods
Based on the large-scale prospective cohort of approximately 420,000 samples from UK Biobank, we firstly investigated the phenotypic correlations. Then, by leveraging the genome-wide summary statistics of cholelithiasis (N = 334,277) and GERD (N = 332,601), we evaluated the bidirectional causal associations between them. Subsequently, we applied a series of genetic analyses to assess the global and local genetic correlation, shared loci and genes between cholelithiasis and GERD to further explore the underlying genetic connections.
Results
Findings from the prospective cohort study revealed a significant increased risk of GERD in individuals with cholelithiasis (Hazard ratio (HR) = 1.99, 95% confidence interval (CI) = 1.89-2.10). Additionally, participants with GERD had a higher risk of incident cholelithiasis (HR = 2.30, 95% CI = 2.18-2.44). The Mendelian randomization study indicated the causal effect of genetic liability to cholelithiasis on the incidence of GERD (Odds ratio = 1.07, 95% CI = 1.05-1.10). Besides, cholelithiasis and GERD exhibited a strong genetic association. Cross-trait meta-analyses identified 5 novel independent loci shared between cholelithiasis and GERD. Three shared genes including SUN2, CBY1 and JOSD1 were further identified as novel risk genes in the transcriptome-wide association studies.
Conclusions
Our comprehensive cohort study and genetic analyses have demonstrated a significant causal association between cholelithiasis and GERD. The elucidation of the shared genetic basis underlying the phenotypic relationship of these two complex phenotypes offers new insights into the intrinsic linkage between cholelithiasis and GERD, encouraging future research on their biological mechanisms and novel therapeutic strategies.