Sedentary lifestyle, physical activity, and gastrointestinal diseases: evidence from mendelian randomization analysis

Abstract

Background: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations.

Methods: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 × 10^-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures.

Findings: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases.

Interpretation: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases.

Funding: Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).

Keywords: Gastrointestinal diseases; Leisure screen time; Mendelian randomization; Physical activity; Sedentary lifestyle.

Fig. 1

Study design. MVPA, moderate-to-vigorous intensity physical activity during leisure time; MR, Mendelian randomization; GERA Resource for Genetic Epidemiology Research on Aging; IIBDGC, the International Inflammatory Bowel Disease Genetics Consortium; MR-PRESSO, Mendelian randomization pleiotropy residual sum, and outlier; BMI, body mass index; WHR, waist to hip ratio.

Fig. 2

Associations of genetically predicted leisure screen time with 24 gastrointestinal diseases in univariable Mendelian randomization and multivariable Mendelian randomization (adjustment for moderate-to-vigorous intensity physical activity). ∗ Significant association after multiple testing. The estimate of irritable bowel syndrome was meta-analyzed by combining estimates from the UK Biobank study, the FinnGen study, and the Genetic Epidemiology Research on Aging consortium; the estimates of Crohn’s disease and ulcerative colitis were meta-analyzed by combining estimates from the UK Biobank study, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium; the estimates of other gastrointestinal disease were meta-analysis by combining estimates from the UK Biobank study and the FinnGen study. ORs for gastrointestinal diseases were scaled to genetically predicted one standard deviation increase in hours/day of leisure screen time.

Fig. 3

Associations of genetically predicted moderate-to-vigorous intensity physical activity with 24 gastrointestinal diseases in univariable Mendelian randomization and multivariable Mendelian randomization (adjustment for leisure screen time). ∗ Significant association after multiple testing. The estimate of irritable bowel syndrome was meta-analyzed by combining estimates from the UK Biobank study, the FinnGen study, and the Genetic Epidemiology Research on Aging consortium; the estimates of Crohn’s disease and ulcerative colitis were meta-analyzed by combining estimates from the UK Biobank study, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium; the estimates of other gastrointestinal disease were meta-analysis by combining estimates from the UK Biobank study and the FinnGen study. ORs for gastrointestinal diseases were scaled to genetically predicted one unit increase in log odds of moderate-to-vigorous intensity physical activity.