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Background Cardiometabolic diseases are highly comorbid, but their relationship with female‐specific or overwhelmingly female‐predominant health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. This study aimed to estimate the cross‐trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to women. Methods and Results Using electronic health record data from 71 008 ancestrally diverse women, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index, coronary artery disease, type 2 diabetes, and hypertension) by performing 4 analyses: (1) cross‐trait genetic correlation analyses to compare genetic architecture, (2) polygenic risk score–based association tests to characterize shared genetic effects on disease risk, (3) Mendelian randomization for significant associations to assess cross‐trait causal relationships, and (4) chronology analyses to visualize the timeline of events unique to groups of women with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age. We observed 27 significant associations between cardiometabolic polygenic scores and obstetrical/gynecological conditions (body mass index and endometrial cancer, body mass index and polycystic ovarian syndrome, type 2 diabetes and gestational diabetes, type 2 diabetes and polycystic ovarian syndrome). Mendelian randomization analysis provided additional evidence of independent causal effects. We also identified an inverse association between coronary artery disease and breast cancer. High cardiometabolic polygenic scores were associated with early development of polycystic ovarian syndrome and gestational hypertension. Conclusions We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female‐specific health conditions.

Understanding the genetic underpinnings of disabling hearing loss, which affects ∼466 million people worldwide, can provide avenues for new therapeutic target development. We performed a genome-wide association meta-analysis of hearing loss with 125,749 cases and 469,497 controls across five cohorts, including UK Biobank, Geisinger DiscovEHR, the Malmö Diet and Cancer Study, Mount Sinai’s BioMe Personalized Medicine Cohort, and FinnGen. We identified 53 loci affecting hearing loss risk, 15 of which are novel, including common coding variants in COL9A3 and TMPRSS3. Through exome-sequencing of 108,415 cases and 329,581 controls from the same cohorts, we identified hearing loss associations with burden of rare coding variants in FSCN2 (odds ratio [OR] = 1.14, P = 1.9 × 10−15) and burden of predicted loss-of-function variants in KLHDC7B (OR = 2.14, P = 5.2 × 10−30). We also observed single-variant and gene-burden associations with 11 genes known to cause Mendelian forms of hearing loss, including an increased risk in heterozygous carriers of mutations in the autosomal recessive hearing loss genes GJB2 (Gly12fs; OR = 1.21, P = 4.2 × 10−11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10−17). Our results suggest that loss of KLHDC7B function increases risk for hearing loss, and show that Mendelian hearing loss genes contribute to the burden of hearing loss in the adult population, suggesting a shared etiology between common and rare forms of hearing loss. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common traits in which risk is modulated by both common and rare variation.

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5x10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.