Sex modifies the effect of genetic risk scores for polycystic ovary syndrome on metabolic phenotypes
Year: 2023
Type: article
Study design: Observational Study
Abstract: Females with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, have an increased risk of developing cardiometabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). While only diagnosable in females, males with a family history of PCOS can also exhibit a poor cardiometabolic profile. Therefore, we aimed to elucidate the role of sex in the cardiometabolic comorbidities observed in PCOS by conducting bidirectional genetic risk score analyses in both sexes. We first conducted a phenome-wide association study (PheWAS) using PCOS polygenic risk scores (PCOSPRS) to identify potential pleiotropic effects of PCOSPRS across 1,380 medical conditions recorded in the Vanderbilt University Medical Center electronic health record (EHR) database, in females and males. After adjusting for age and genetic ancestry, we found that European (EUR)-ancestry males with higher PCOSPRS were significantly more likely to develop hypertensive diseases than females at the same level of genetic risk. We performed the same analysis in an African (AFR)-ancestry population, but observed no significant associations, likely due to poor trans-ancestry performance of the PRS. Based on observed significant associations in the EUR-ancestry population, we then tested whether the PRS for comorbid conditions (e.g., T2D, body mass index (BMI), hypertension, etc.) also increased the odds of a PCOS diagnosis. Only BMIPRS and T2DPRS were significantly associated with a PCOS diagnosis in EUR-ancestry females. We then further adjusted the T2DPRS for measured BMI and BMIresidual (regressed on the BMIPRS and enriched for the environmental contribution to BMI). Results demonstrated that genetically regulated BMI primarily accounted for the relationship between T2DPRS and PCOS. Overall, our findings show that the genetic architecture of PCOS has distinct sex differences in associations with genetically correlated cardiometabolic traits. It is possible that the cardiometabolic comorbidities observed in PCOS are primarily explained by their shared genetic risk factors, which can be further influenced by biological variables including sex and BMI.
Source: PLoS Genetics
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,655
Funders: Vanderbilt University, Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, Office of Research on Women's Health, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Investigating the genetic and clinical determinants of polycystic ovary syndrome, Pharmacogenomics of Arrhythmia Therapy, G1531600799, Center of Excellence in Precision Medicine and Population Health, Understanding the genetic risk underlying racial disparities in uterine fibroids, G2533431092, G2537422520, G2615776415, G2635992203, G2683268942, Improving Prediction of Drug Action, G3395468139, G3619590958, G364208108, Automated Storage and Retrieval of Biological Systems, G4410787187, BioVU Plasma Storage Equipment, G560889077, G5679716143, Genetic Epidemiology of Multiple Sclerosis, Elucidating the phenome-wide impact of sex and gender on disease, G6589054092, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, Understanding determinants of racial disparities in lung cancer incidence, VESPA: Vanderbilt Electronic Systems for Pharmacogenomic Assessment, G7412434281, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Vanderbilt Genome Electronic Records Project, Epidemiologic Architecture for Genes Linked to Environment (EAGLE), G8332127685, Vanderbilt Institute for Clinical and Translational Research (VICTR), Addressing racial disparities in lung cancer screening
OpenAlex ID: W4378902251