Inference of causal relationships between genetic risk factors for cardiometabolic phenotypes and female-specific health conditions

Abstract Cardiometabolic diseases are highly comorbid, but their relationship with female-specific health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. Using electronic health record data from 71,008 ancestrally diverse females, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index [BMI], coronary artery disease [CAD], type 2 diabetes [T2D], and hypertension) using cross-trait genetic correlation analyses, polygenic risk scores (PRSs), Mendelian randomization (MR), and chronology analyses. We observed 29 significant associations between cardiometabolic PRSs and obstetrical/gynecological conditions (BMI and endometrial cancer; BMI and polycystic ovarian syndrome [PCOS)]; T2D and gestational diabetes; T2D and PCOS). MR analysis provided additional evidence of independent causal effects. We also identified an inverse association between CAD and breast cancer. High cardiometabolic PRSs were associated with early development of PCOS and gestational hypertension. We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female-specific health conditions.