Inference of causal relationships based on the genetics of cardiometabolic traits and conditions unique to females in >50,000 participants

Background Cardiometabolic diseases are highly comorbid and associated with poor health outcomes. However, the investigation of the relationship between the genetic predisposition to cardiometabolic diseases with the risk of conditions unique to females such as breast cancer, endometriosis and pregnancy-related complications is highly understudied. This study aimed to estimate the cross-trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to females. Methods We obtained data for female participants in the Penn Medicine BioBank (PMBB; 21,837 samples) and the electronic MEdical Records and GEnomics (eMERGE; 49,171 samples) network. We examined the relationship between four cardiometabolic phenotypes (body mass index (BMI), coronary artery disease (CAD), type 2 diabetes (T2D) and hypertension (through blood pressure measurements)) and 23 female health conditions by performing four analyses: 1) Cross-trait genetic correlation analyses to compare genetic architecture. 2) Polygenic risk scores (PRS)-based association tests to characterize shared genetic effects on disease risk. 3) Mendelian randomization (MR) for significant associations to assess cross-trait causal relationships. 4) Chronology analyses to visualize the timeline of events unique to groups of females with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age. Results We observed high genetic correlation among cardiometabolic and female health conditions. PRS meta-analysis identified 29 significant associations reflecting potential shared biology among common cardiometabolic phenotypes and female health conditions. Significant associations include PRSBMI with endometrial cancer and polycystic ovarian syndrome (PCOS), PRSCAD with breast cancer, and the PRST2D with gestational diabetes and PCOS. Mendelian randomization provided additional evidence of independent causal effects between T2D and gestational diabetes and CAD and with breast cancer. Our results reflected inverse association between PRSCAD and breast cancer. Lastly, as visualized from chronology analyses, individuals with high PRS are also more likely to develop conditions such as PCOS and gestational hypertension at earlier ages. Conclusions Polygenic susceptibility to cardiometabolic traits is associated with conditions unique to females. Several of these associations are likely to result from the complex pathophysiology of cardiometabolic risk, and others may reflect potential pleiotropic effects that go beyond cardiometabolic health in females. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The eMERGE Network was initiated and funded by NHGRI through the following grants: Phase IV: U01HG011172 (Cincinnati Children's Hospital Medical Center); U01HG011175 (Children's Hospital of Philadelphia); U01HG008680 (Columbia University); U01HG011176 (Icahn School of Medicine at Mount Sinai); U01HG008685 (Mass General Brigham); U01HG006379 (Mayo Clinic); U01HG011169 (Northwestern University); U01HG011167 (University of Alabama at Birmingham); U01HG008657 (University of Washington Medical Center, Seattle); U01HG011181 (Vanderbilt University Medical Center); U01HG011166 (Vanderbilt University Medical Center serving as the Coordinating Center) Phase III: U01HG8657 (Kaiser Permanente Washingtom/University of Washington Medical Center); U01HG8685 (Brigham and Women's Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children's Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children's Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine). ### 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: eMERGE data: It is openly accessible data and can be downloaded from dbGAP. Penn Medicine BioBank data: Individual-level data cannot be made available through dbGaP or other public repositories for compliance with IRB protocol to protect patient confidentiality. Approval for the Penn Medicine BioBank was given from the University of Pennsylvania Institutional Review Board. The PMBB study has been determined to pose minimal risk to subjects. Summary stats and SNP scores for polygenic risk scores will be made available through dbGAP after the approval of the manuscript. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in this study are available upon request to the authors. Summary level data will also be available upon request.