Understanding and Predicting Polycystic Ovary Syndrome through Shared Genetic Architecture with Testosterone, SHBG, and Inflammatory Markers

Polycystic ovary syndrome (PCOS) is a common hormonal disorder that affects one out of eight women and has high metabolic and psychological comorbidities. PCOS is thought to be associated with obesity, hormonal dysregulation, and systemic low-grade inflammation, but the underlying mechanisms remain unclear. Here we study the genetic relationship between PCOS and obesity, testosterone, sex hormone binding globulin (SHBG), and a wide-range of inflammatory markers. First, we created a large meta-analysis of PCOS (7,747 PCOS cases and 498,227 controls) and identified four novel genetic loci associated with PCOS. These novel loci have been previously associated with gene expression in multiple PCOS-relevant tissues including the thyroid and ovary. We then further incorporated GWASs for obesity (n=681,275), SHBG (n=190,366), testosterone (n=176,687), and 138 inflammatory biomarkers (average n=30,000). Using Mendelian randomization methods, we replicated genetic causal relationships from obesity and SHBG to PCOS. We identified significant genetic correlations between PCOS and eleven inflammatory biomarkers, including novel and strong correlations with death receptor 5 (LDSC rg = 0.54, FDR = 0.043), among others. Although no statistically significant causal relationship was observed between inflammatory markers and PCOS, 31 inflammatory biomarkers showed significant causal effects on SHBG or testosterone, supporting a potentially etiological role of chronic inflammation in influencing sex hormone levels. Finally, we show that combining the polygenic risk scores of PCOS and PCOS-related traits improves genetic prediction of PCOS cases in the UK Biobank and MGB Biobank, as compared to using only the risk score of PCOS. Together, these results support the theory that immune responses are altered in PCOS patients and that chronic inflammation may play a role in testosterone dysregulation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement LKP gratefully acknowledges the support of the U.S. Department of Energy (DOE) through the Los Alamos National Laboratory (LANL) LDRD Program and the Center for Nonlinear Studies, and GB gratefully acknowledges the support of the Harvard College Research Program. The Nurses Health Study, Nurses Health Study II, and Health Professionals Follow-up Study are supported by NIH grants UM1CA186107, R01CA49449, U01CA176726, R01CA67262, and U01CA167552. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study used data from the UK Biobank (available to authorized researchers at ), the Mass General Brigham Biobank (upon approval of an Institutional Review Board), and the Nurses Health Study (approved by internal review). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors