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

• Published in: PLoS medicine Vol. 19; no. 2; p. e1003679
• Main Authors: Venkatesh, Samvida S, Ferreira, Teresa, Benonisdottir, Stefania, Rahmioglu, Nilufer, Becker, Christian M, Granne, Ingrid, Zondervan, Krina T, Holmes, Michael V, Lindgren, Cecilia M, Wittemans, Laura B L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2022; Public Library of Science (PLoS)
• Subjects: Adipose tissue; Adult; Age; Aged; Bias; Biobanks; Biology and Life Sciences; Bleeding; Body fat; Body mass index; Body weight; Complications and side effects; Development and progression; Disease; Endometriosis; Epidemiology; Female; Females; Fibroids; Genome-Wide Association Study; Genomes; Gynecology; Health aspects; Hip; Humans; Infertility; Infertility, Female; Insulin; Insulin resistance; Leiomyoma - epidemiology; Leiomyoma - etiology; Leiomyoma - genetics; Leptin; Male; Medicine and Health Sciences; Mendelian Randomization Analysis; Menstruation; Metabolism; Middle Aged; Miscarriage; Obesity; Obesity - complications; Obesity - epidemiology; Obesity - genetics; Overweight; Peer review; Physiological aspects; Pleiotropy; Polycystic ovary syndrome; Polycystic Ovary Syndrome - epidemiology; Polycystic Ovary Syndrome - etiology; Polycystic Ovary Syndrome - genetics; Pre-eclampsia; Pre-Eclampsia - epidemiology; Pre-Eclampsia - etiology; Pre-Eclampsia - genetics; Preeclampsia; Pregnancy; Regression analysis; Reproductive system; Risk Assessment; Risk factors; United Kingdom - epidemiology; Uterine Hemorrhage - epidemiology; Uterine Hemorrhage - etiology; Uterine Hemorrhage - genetics; Uterus; Womens health; United Kingdom; United Kingdom > UK
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1003679

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.