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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>\n                      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\u20131.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06\u20132.09) 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\u20131.64],\n                      <jats:italic>P<\/jats:italic>\n                      = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08\u20131.23],\n                      <jats:italic>P<\/jats:italic>\n                      = 3.24 \u00d7 10\n                      <jats:sup>\u221205<\/jats:sup>\n                      ), and pre-eclampsia (OR [95% CI] = 3.08 [1.98\u20134.79],\n                      <jats:italic>P<\/jats:italic>\n                      = 6.65 \u00d7 10\n                      <jats:sup>\u221207<\/jats:sup>\n                      ). Increased waist circumference posed a higher genetic risk (ORs = 1.16\u20131.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06\u20131.10). 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pmed.1003679","type":"journal-article","created":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T13:22:51Z","timestamp":1643721771000},"page":"e1003679","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":170,"title":["Obesity and risk of female reproductive conditions: A Mendelian randomisation study"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7680-1208","authenticated-orcid":true,"given":"Samvida S.","family":"Venkatesh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Benonisdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5169-8571","authenticated-orcid":true,"given":"Nilufer","family":"Rahmioglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9870-9581","authenticated-orcid":true,"given":"Christian M.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7056-5723","authenticated-orcid":true,"given":"Ingrid","family":"Granne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0275-9905","authenticated-orcid":true,"given":"Krina T.","family":"Zondervan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-0879","authenticated-orcid":true,"given":"Michael V.","family":"Holmes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4903-9374","authenticated-orcid":true,"given":"Cecilia M.","family":"Lindgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6588-938X","authenticated-orcid":true,"given":"Laura B. 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Diamanti-Kandarakis","year":"2007","journal-title":"Int J Obes (Lond)."},{"key":"pmed.1003679.ref006","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.metabol.2018.11.002","article-title":"Characteristics of obesity in polycystic ovary syndrome: etiology, treatment, and genetics","volume":"92","author":"CJ Glueck","year":"2019","journal-title":"Metabolism"},{"issue":"1","key":"pmed.1003679.ref007","doi-asserted-by":"crossref","first-page":"R5","DOI":"10.1152\/ajpregu.00440.2016","article-title":"Metabolic abnormalities and obesity\u2019s impact on the risk for developing preeclampsia","volume":"312","author":"FT Spradley","year":"2017","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"7","key":"pmed.1003679.ref008","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1093\/humrep\/deh277","article-title":"Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study","volume":"19","author":"H Lashen","year":"2004","journal-title":"Hum Reprod"},{"issue":"1","key":"pmed.1003679.ref009","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.fertnstert.2009.03.021","article-title":"Body mass index and risk of miscarriage in women with recurrent miscarriage","volume":"94","author":"M Metwally","year":"2010","journal-title":"Fertil Steril"},{"issue":"2","key":"pmed.1003679.ref010","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1093\/humrep\/dem371","article-title":"Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women","volume":"23","author":"JW van der Steeg","year":"2008","journal-title":"Hum Reprod"},{"issue":"1","key":"pmed.1003679.ref011","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1093\/humrep\/dep360","article-title":"An internet-based prospective study of body size and time-to-pregnancy","volume":"25","author":"LA Wise","year":"2010","journal-title":"Hum 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polycystic ovary syndrome","volume":"34","author":"MA Brower","year":"2019","journal-title":"Hum Reprod"},{"issue":"6","key":"pmed.1003679.ref019","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1093\/humrep\/deg233","article-title":"Inverse correlation between peritoneal fluid leptin concentrations and the extent of endometriosis","volume":"18","author":"NG Mahutte","year":"2003","journal-title":"Hum Reprod"},{"issue":"5","key":"pmed.1003679.ref020","first-page":"517","article-title":"Further studies on leptin and leptin receptor expression in myometrium and uterine myomas","volume":"26","author":"A Markowska","year":"2005","journal-title":"Eur J Gynaecol Oncol"},{"issue":"9","key":"pmed.1003679.ref021","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1093\/humrep\/16.9.1819","article-title":"Baseline non-fasting serum leptin concentration to body mass index ratio is predictive of IVF outcomes","volume":"16","author":"JD Brannian","year":"2001","journal-title":"Hum Reprod"},{"issue":"2","key":"pmed.1003679.ref022","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/osp4.399","article-title":"Preconception leptin levels and pregnancy outcomes: a prospective cohort study.","volume":"6","author":"TC Plowden","year":"2020","journal-title":"Obes Sci Pract"},{"issue":"11","key":"pmed.1003679.ref023","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1097\/OGX.0000000000000718","article-title":"Cardiometabolic risk factors and benign gynecologic disorders.","volume":"74","author":"A AlAshqar","year":"2019","journal-title":"Obstet Gynecol Surv"},{"issue":"4","key":"pmed.1003679.ref024","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.ajog.2011.02.024","article-title":"Maternal insulin resistance and preeclampsia.","volume":"204","author":"JC Hauth","year":"2011","journal-title":"Am J Obstet Gynecol"},{"issue":"4","key":"pmed.1003679.ref025","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s10815-014-0411-0","article-title":"Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction","volume":"32","author":"MG Butler","year":"2015","journal-title":"J Assist Reprod Genet"},{"issue":"3","key":"pmed.1003679.ref026","doi-asserted-by":"crossref","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.","volume":"12","author":"C Sudlow","year":"2015","journal-title":"PLoS Med."},{"issue":"8","key":"pmed.1003679.ref027","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.jclinepi.2014.03.012","article-title":"False discovery rate control is a recommended alternative to Bonferroni-type adjustments in health studies.","volume":"67","author":"ME Glickman","year":"2014","journal-title":"J Clin Epidemiol"},{"issue":"1","key":"pmed.1003679.ref028","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing.","volume":"57","author":"Y Benjamini","year":"1995","journal-title":"J R Stat Soc B Stat Methodol"},{"key":"pmed.1003679.ref029","doi-asserted-by":"crossref","first-page":"k1767","DOI":"10.1136\/bmj.k1767","article-title":"Role of obesity in smoking behaviour: Mendelian randomisation study in UK Biobank","volume":"361","author":"R Carreras-Torres","year":"2018","journal-title":"BMJ"},{"key":"pmed.1003679.ref030","unstructured":"Ambler GB, Axel. mfp: multivariable fractional polynomials. Version 1.5.2. Comprehensive R Archive Network; 2015."},{"key":"pmed.1003679.ref031","unstructured":"Wood S. mgcv: mixed GAM computation vehicle with automatic smoothness estimation. Version 1.8\u201331. Comprehensive R Archive Network; 2021."},{"issue":"1","key":"pmed.1003679.ref032","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1538-4632.1995.tb00333.x","article-title":"Generalized additive models, graphical diagnostics, and logistic regression.","volume":"27","author":"K Jones","year":"1995","journal-title":"Geogr Anal."},{"key":"pmed.1003679.ref033","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4612-1694-0_15","volume-title":"Information theory and an extension of the maximum likelihood principle","author":"H. Akaike","year":"1998"},{"issue":"1","key":"pmed.1003679.ref034","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/hmg\/ddy327","article-title":"Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry","volume":"28","author":"SL Pulit","year":"2019","journal-title":"Hum Mol Genet"},{"issue":"9","key":"pmed.1003679.ref035","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1038\/s41591-019-0563-7","article-title":"Contribution of genetics to visceral adiposity and its relation to cardiovascular and metabolic disease","volume":"25","author":"T Karlsson","year":"2019","journal-title":"Nat Med"},{"key":"pmed.1003679.ref036","article-title":"The MRC IEU OpenGWAS data infrastructure.","author":"B Elsworth","year":"2020","journal-title":"bioRxiv"},{"issue":"24","key":"pmed.1003679.ref037","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1001\/jama.2018.19329","article-title":"Association of genetic variants related to gluteofemoral vs abdominal fat distribution with type 2 diabetes, coronary disease, and cardiovascular risk factors.","volume":"320","author":"LA Lotta","year":"2018","journal-title":"JAMA"},{"issue":"1","key":"pmed.1003679.ref038","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1093\/ije\/dyx206","article-title":"Collider scope: when selection bias can substantially influence observed associations.","volume":"47","author":"MR Munafo","year":"2018","journal-title":"Int J Epidemiol"},{"key":"pmed.1003679.ref039","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/s41588-021-00846-7","article-title":"Genetic analyses identify widespread sex-differential participation bias.","volume":"53","author":"N Pirastu","year":"2021","journal-title":"Nat Genet"},{"issue":"7538","key":"pmed.1003679.ref040","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature14177","article-title":"Genetic studies of body mass index yield new insights for obesity biology","volume":"518","author":"AE Locke","year":"2015","journal-title":"Nature"},{"issue":"7538","key":"pmed.1003679.ref041","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/nature14132","article-title":"New genetic loci link adipose and insulin biology to body fat distribution","volume":"518","author":"D Shungin","year":"2015","journal-title":"Nature"},{"issue":"5","key":"pmed.1003679.ref042","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1093\/ije\/dyaa266","article-title":"Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations.","volume":"50","author":"FP Hartwig","year":"2021","journal-title":"Int J Epidemiol."},{"issue":"9","key":"pmed.1003679.ref043","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1038\/s41588-018-0184-y","article-title":"Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies","volume":"50","author":"W Zhou","year":"2018","journal-title":"Nat Genet"},{"issue":"17","key":"pmed.1003679.ref044","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1093\/bioinformatics\/btq340","article-title":"METAL: fast and efficient meta-analysis of genomewide association scans","volume":"26","author":"CJ Willer","year":"2010","journal-title":"Bioinformatics"},{"issue":"11","key":"pmed.1003679.ref045","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1158\/1055-9965.EPI-16-0147","article-title":"Genetic risk score Mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer","volume":"25","author":"JN Painter","year":"2016","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"1","key":"pmed.1003679.ref046","doi-asserted-by":"crossref","first-page":"5980","DOI":"10.1038\/s41467-020-19742-5","article-title":"The genetic architecture of sporadic and multiple consecutive miscarriage.","volume":"11","author":"T Laisk","year":"2020","journal-title":"Nat Commun"},{"issue":"12","key":"pmed.1003679.ref047","doi-asserted-by":"crossref","first-page":"e1007813","DOI":"10.1371\/journal.pgen.1007813","article-title":"Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.","volume":"14","author":"F Day","year":"2018","journal-title":"PLoS Genet"},{"issue":"3","key":"pmed.1003679.ref048","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/gepi.22284","article-title":"Power calculation for the general two-sample Mendelian randomization analysis","volume":"44","author":"L Deng","year":"2020","journal-title":"Genet Epidemiol"},{"issue":"5","key":"pmed.1003679.ref049","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1093\/ije\/dyt179","article-title":"Calculating statistical power in Mendelian randomization studies.","volume":"42","author":"MJ Brion","year":"2013","journal-title":"Int J 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Bycroft","year":"2018","journal-title":"Nature"},{"issue":"4","key":"pmed.1003679.ref056","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/gepi.22041","article-title":"Semiparametric methods for estimation of a nonlinear exposure-outcome relationship using instrumental variables with application to Mendelian randomization","volume":"41","author":"JR Staley","year":"2017","journal-title":"Genet Epidemiol"},{"key":"pmed.1003679.ref057","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s10654-021-00757-1","article-title":"Mendelian randomisation for mediation analysis: current methods and challenges for implementation.","volume":"36","author":"AR Carter","year":"2021","journal-title":"Eur J Epidemiol"},{"key":"pmed.1003679.ref058","doi-asserted-by":"crossref","first-page":"10494","DOI":"10.1038\/ncomms10494","article-title":"Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.","volume":"7","author":"TO Kilpelainen","year":"2016","journal-title":"Nat Commun."},{"issue":"6","key":"pmed.1003679.ref059","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/ng.2274","article-title":"A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance","volume":"44","author":"AK Manning","year":"2012","journal-title":"Nat Genet"},{"issue":"10","key":"pmed.1003679.ref060","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.2337\/db16-0199","article-title":"Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci","volume":"65","author":"GA Walford","year":"2016","journal-title":"Diabetes"},{"issue":"11","key":"pmed.1003679.ref061","doi-asserted-by":"crossref","first-page":"e1007081","DOI":"10.1371\/journal.pgen.1007081","article-title":"Orienting the causal relationship between imprecisely measured traits using GWAS 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Makabe","year":"2019","journal-title":"Carcinogenesis"},{"issue":"4","key":"pmed.1003679.ref076","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1111\/cen.14421","article-title":"Obesity and polycystic ovary syndrome","volume":"95","author":"TM Barber","year":"2021","journal-title":"Clin Endocrinol (Oxf)."},{"issue":"8","key":"pmed.1003679.ref077","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1002\/oby.20213","article-title":"Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women.","volume":"21","author":"HJ Teede","year":"2013","journal-title":"Obesity (Silver Spring)."},{"key":"pmed.1003679.ref078","doi-asserted-by":"crossref","first-page":"185","DOI":"10.2147\/CLEP.S129879","article-title":"Confounding in observational studies based on large health care databases: problems and potential solutions\u2014a primer for the clinician.","volume":"9","author":"M Norgaard","year":"2017","journal-title":"Clin Epidemiol"},{"issue":"5","key":"pmed.1003679.ref079","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1097\/EDE.0b013e3181810e29","article-title":"Causal directed acyclic graphs and the direction of unmeasured confounding bias.","volume":"19","author":"TJ VanderWeele","year":"2008","journal-title":"Epidemiology"},{"issue":"6","key":"pmed.1003679.ref080","doi-asserted-by":"crossref","first-page":"E1088","DOI":"10.1210\/jc.2013-1295","article-title":"Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome","volume":"98","author":"U Ezeh","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"pmed.1003679.ref081","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1530\/EJE-15-0646","article-title":"Referral bias in female functional hyperandrogenism and polycystic ovary syndrome","volume":"173","author":"M Luque-Ramirez","year":"2015","journal-title":"Eur J 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