Association of education with cholelithiasis and mediating effects of cardiometabolic factors: A Mendelian randomization study

Abstract

BACKGROUND

Education, cognition, and intelligence are associated with cholelithiasis occurrence, yet which one has a prominent effect on cholelithiasis and which cardiometabolic risk factors mediate the causal relationship remain unelucidated.

AIM

To explore the causal associations between education, cognition, and intelligence and cholelithiasis, and the cardiometabolic risk factors that mediate the associations.

METHODS

Applying genome-wide association study summary statistics of primarily European individuals, we utilized two-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 two-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 [odds ratio: 0.292 (95%CI: 0.171-0.501)], 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%). All results were robust to sensitivity analyses.

CONCLUSION

Education, cognition, and intelligence all play crucial roles in the development of cholelithiasis, and several cardiometabolic mediators have been identified for prevention of cholelithiasis due to defects in each exposure.

Keywords: Cholelithiasis; Mendelian randomization; Mediation analysis; Education attainment; Cardiometabolic risk factors; Cognition; Intelligence

Core Tip: In this study, we investigated the independent causal effects of education, cognition, and intelligence on cholelithiasis and cholecystitis. Subsequently, we estimated the independent association between each exposure and cholecystitis, after adjustment for cholelithiasis. Finally, the ultimate aims were to screen out the mediator(s) and clarify the mediating effects of several correlated risk factors in the pathogenesis of cholelithiasis to instrument clinical practice.