Associations of Education with Cholelithiasis and the Mediating Effects of Cardiometabolic Factors: A Mendelian Randomization Study

Abstract

Abstract Background Education, cognition and intelligence are associated with cholelithiasis progression, yet which one has a prominent effect on cholelithiasis and which cardiometabolic risk factors mediate the causal relationship remain unelucidated. Method Applying genome-wide association study summary statistics of primarily European individuals, we utilized 2-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, and cognition on cholelithiasis and cholecystitis (FinnGen study, 37041 and 11632 patients, respectively; n = 486484 participants) and performed 2-step Mendelian randomization to evaluate 21 potential mediators and their mediating effects on the relationships, between each exposure and cholelithiasis. Results Inverse variance weighted Mendelian randomization results from the FinnGen consortium showed that genetically higher education, cognition or intelligence were not independently associated with cholelithiasis and cholecystitis; when adjusted for cholelithiasis, higher education still presented an inverse effect on cholecystitis [OR: 0.292 (95% CI: 0.171 to 0.501)], which could not be induced by cognition or intelligence. Five out of 21 cardiometabolic risk factors were perceived as mediators of the association between education and cholelithiasis, including body mass index (20.84%), body fat percentage (40.3%), waist circumference (44.4%), waist-to-hip ratio (32.9%) and time spent watching television (41.6%); while time spent watching television was also a mediator from cognition (20.4%) and intelligence to cholelithiasis (28.4%). These results above were all robust to sensitivity analyses. Conclusion Education, cognition and intelligence all played crucial roles in the development of cholelithiasis, and several cardiometabolic mediators were identified as inferior targets for prevention of cholelithiasis due to defects in each exposure.