Abstract
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. 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. 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.
Highlights
Obesity is commonly understood as the excess accumulation of body fat, which leads to increased health risks
Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for body mass index (BMI) were observationally and genetically (ORs = 1.06–2.09) associated with uterine fibroids (UF), polycystic ovary syndrome (PCOS), heavy menstrual bleeding (HMB), and pre-eclampsia
We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, largescale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions
Summary
Obesity is commonly understood as the excess accumulation of body fat, which leads to increased health risks. In women, increased body mass index (BMI) is associated with increased prevalence of gynaecological conditions, including excessive and abnormal menstrual bleeding [1,2], endometriosis and uterine fibroids (UF) [3,4], polycystic ovary syndrome (PCOS) [5,6], complications of pregnancy such as pre-eclampsia and eclampsia [7], miscarriage [8,9], and infertility [10,11]. These are often non-linear and heterogeneous relationships. We aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders
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