Obesity and risk of female reproductive conditions: A Mendelian randomisation study

Abstract

Background Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders. Methods and findings Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02–1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06–2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06–1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08–1.23], P = 3.24 × 10−05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98–4.79], P = 6.65 × 10−07). Increased waist circumference posed a higher genetic risk (ORs = 1.16–1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06–1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy. Conclusions We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.

The Complex Roles of Adipokines in Polycystic Ovary Syndrome and Endometriosis

“…Low overall adiposity and a preferred localization of fat below the waist were found to be related to endometriosis [ 232 ]. The risk of endometriosis is higher for females being thinner than average at an age of about 10 years [ 233 ]. In later life, abdominal fat distribution contributes to the development of endometriosis [ 233 ].…”

ASPN Is a Potential Biomarker and Associated with Immune Infiltration in Endometriosis

“…Lasso regression is a machine learning algorithm to obtain a more compact model by constructing a penalty function, which has a unique advantage for handling complex covariance data and is now commonly used for variable filtering and model complexity reduction [ 19 , 20 ]. The generalized linear model is an extension of the traditional linear model, an algorithm in which the overall mean is passed through a nonlinear connectivity function to handle and take non-normally distributed data well [ 21 ]. To screen out the best biomarkers for endometriosis, we used the Lasso regression algorithm to identify 26 variables as potential diagnostic markers from 38 DEGs ( Figure 2 A,B).…”

The HIF2α polymorphism rs4953361 is associated with impaired glucose metabolism in Han Chinese women with infertility

“…Here, we observed that elevated BMI, impaired glucose metabolism, and increased levels of plasma insulin were metabolic traits that were characteristic of infertile women. The increasing obesity epidemic, with its related metabolic disorders, is associated with an increased risk of many female reproductive conditions (13). Obesity negatively affects female reproductive health, including increased risks of menstrual dysfunction, anovulation, and other fertility problems (14,15).…”