Supporting data for "Observational, Causal Relationship and Shared Genetic Basis Between Cholelithiasis and Gastroesophageal Reflux Disease: Evidence from a Cohort Study and Comprehensive Genetic Analysis"

Cholelithiasis and gastroesophageal reflux disease (GERD) contribute to significant health concerns. We aimed to investigate the potential observational, causal and genetic relationships between cholelithiasis and GERD. <br>The observational correlations were assessed based on the prospective cohort study from UK Biobank. Then, by leveraging the genome-wide summary statistics of cholelithiasis (N = 334,277) and GERD (N = 332,601), the bidirectional causal associations was evaluated using Mendelian randomization (MR) analysis. Subsequently, a series of genetic analyses was used to assess the genetic correlation, shared loci and genes between cholelithiasis and GERD. <br>The prospective cohort analyses revealed a significant increased risk of GERD in individuals with cholelithiasis (Hazard ratio (HR) = 1.99, 95% confidence interval (CI) = 1.89-2.10) and a higher risk of cholelithiasis among GERD patients (HR = 2.30, 95% CI = 2.18-2.44). The MR study indicated the causal effect of genetic liability to cholelithiasis on the incidence of GERD (Odds ratio (OR) = 1.07, 95% CI = 1.05-1.10) and the causal effect of genetic predicted GERD on cholelithiasis (IVW OR = 1.15, 95% CI = 1.02-1.30). 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 <em>SUN2</em>, <em>CBY1</em>, and <em>JOSD1</em> were further identified as novel risk genes. <br>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, providing a novel research direction for future therapeutic strategy and risk prediction.