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. Using observational and Mendelian randomization approaches, Samvida Venkatesh and colleagues investigate associations between obesity, metabolic factors, and female reproductive conditions. Author summary Why was this study done? Female reproductive disorders are common, yet relatively understudied, conditions with a large impact on women’s health and overall well-being. Obesity has previously been associated with the risk of developing female reproductive conditions, but estimates may be biased by weight gain caused by the disease or its treatment, as well as confounding environmental and lifestyle factors. What did the researchers do and find? In one of the largest publicly available datasets on human health, which includes up to 250,000 women, we saw positive associations between obesity and a range of female reproductive disorders, including uterine fibroids, polycystic ovary syndrome, heavy menstrual bleeding, and pre-eclampsia. We found that inherited genetic variation that is associated with obesity is also associated with female reproductive disorders, but the strength of these associations differs by type of obesity and reproductive condition. As genetic variants are randomly assigned at birth, this is a method to estimate the effect of obesity on reproductive conditions unbiased by environmental and lifestyle factors or reverse causation. Hormones such as leptin, which is secreted by fat cells, and insulin were found to mediate the genetic association of obesity with pre-eclampsia. What do these findings mean? Genetics-based investigations such as these provide support for the role of obesity in increasing the risk of reproductive conditions, reinforcing the need to address rising obesity rates in the population. Increased obesity and insulin resistance are potentially modifiable risk factors, and addressing these risk factors could help mitigate or treat female reproductive disorders, but further research must confirm that their manipulation influences risk of disease.