Abstract
BACKGROUND: Previous observational studies have reported that lifestyle factors, metabolic factors and socioeconomic status are associated with the development of female pelvic organ prolapse (POP); however, whether these associations are causal remains unclear. The current study aimed to assess the causal effect of lifestyle factors, metabolic factors and socioeconomic status on POP risk. METHODS: We conducted a two-sample Mendelian randomization (MR) study based on summary-level data from the largest available genome-wide association studies (GWAS) to evaluate whether lifestyle factors, metabolic factors and socioeconomic status are causally related to POP. We used single nucleotide polymorphisms that are strongly associated with exposure at the genome-wide significance level (P < 5 × 10(-8)) as instrumental variables from genome-wide association studies. The method of random-effect inverse-variance weighting (IVW) was used as the primary analysis method, supplemented with the weighted median, MR-Egger and the MR pleiotropy residual sum and outlier applied to verify the MR assumptions. Two-step MR was conducted to investigate potential intermediate factors that are on the causal pathway from exposure to POP. RESULTS: There were associations with POP for genetically predicted waist-to-hip ratio (WHR) (odds ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.03 per SD-increase, P < 0.001), WHR adjusted for body mass index (WHRadjBMI) (OR 1.017, 95% CI 1.01-1.025 per SD-increase, P < 0.001) and education attainment (OR 0.986, 95% CI 0.98-0.991 per SD-increase) in the meta-analysis. Additionally, genetically predicted coffee consumption (OR per 50% increase 0.67, 95% CI 0.47-0.96, P = 0.03), vigorous physical activity (OR 0.83, 95% CI 0.69-0.98, P = 0.043) and high-density lipoprotein cholesterol (HDL-C) (OR 0.91, 95% CI 0.84-0.98 per SD-increase, P = 0.049) were inversely associated with POP in the FinnGen Consortium. The mediation analysis showed that the indirect effects of education attainment on POP were partly mediated by WHR and WHRadjBMI, with a mediated proportion of 27% and 13% in the UK Biobank study, respectively. CONCLUSIONS: Our study provides MR evidence of a robust causal association of WHR, WHRadjBMI and education attainment with POP.