Both general- and central- obesity are causally associated with polycystic ovarian syndrome: Findings of a Mendelian randomization study

ABSTRACT Introduction Obesity is observed in a majority of women with polycystic ovarian syndrome (PCOS). Using body mass index (BMI) as a proxy, previous Mendelian randomization studies revealed general obesity potentially causes PCOS. Central obesity frequently demonstrates a stronger association with PCOS, although evidence on its causality is sparse. Objectives To investigate causal effects of both central- and general- obesity on the development of PCOS via two-sample Mendelian randomization (2SMR). Methods Summary: GWAS data of female-only, large-sample cohorts of European ancestry were retrieved for anthropometric markers of central obesity (waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR)) and general obesity (BMI and its constituent variables – weight and height), from the IEU Open GWAS Project. As the outcome data, we acquired summary data from a large-sample GWAS (96391 samples; 219 cases and 96172 controls) from the FinnGen cohort. Four 2SMR methods were applied: inverse variance weighted (IVW); MR Egger (MRE); weighted median (WME); weighted mode (WMO). Single SNP-, leave-one-out-, heterogeneity-, horizontal pleiotropy- and outlier- analyses were conducted. Genetic architectures underlying causal associations were explored. Results All SNPs selected as instrumental variables demonstrated no weak instrument bias (F > 10). Three anthropometric exposures, namely, BMI (OR: 5.55 – 7.24, WC (OR: 6.79 – 24.56), and HC (OR: 6.78 – 24.56), significantly causally associated with PCOS as per IVW, WME, and WMO models. Single SNP- and leave-one-out- sensitivity analysis results were indicative of robust causal estimates. No significant heterogeneity, horizontal pleiotropy, and outliers were observed. We observed a considerable degree of overlap (7 SNPs; 17 genes) across significant causal findings as well as a number of SNPs and genes that were not shared between causal associations. Conclusions This study revealed that both and general- and central obesity potentially cause PCOS. Findings underscore the importance of addressing obesity and adiposity for the prevention and management of PCOS.