7310 System-level Analysis in Polycystic Ovary Syndrome on a Panel of Genetically Diverse Strains of Mice

Abstract Disclosure: L.M. Velez: None. C. Johnson: None. I. Tamburrini: None. M. Zhou: None. C. Viesi: None. N. Ujagar: None. D. Ashbrook: None. M. Nelson: None. A. Senior: None. D. James: None. R. Williams: None. D. Nicholas: None. M. Seldin: None. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, with a prevalence of ∼4-20% in women of reproductive age. The diagnosis of the syndrome generally occurs when the patient consults for fertility issues and is only based on a reproductive criterion, which includes (1) hyperandrogenism, (2) oligo-anovulation, and (3) polycystic ovary morphology. However, the overlap of PCOS with cardiometabolic diseases is significant. To put in numbers; up to 75% of PCOS women present some degree of insulin insensitivity, 38-88% present obesity or overweight, 20-50% develop type 2 diabetes by age 40, and PCOS women are at increased risk of cardiovascular disease. Despite these facts, shared reproductive/metabolic mechanisms are largely underexplored. Moreover, studies addressing the genetic architecture of PCOS are missing. Here, we induced a PCOS-like condition in 25 recombinant and classical inbred female strains and matched placebo controls over 6 weeks. Comprehensive in vivo and terminal reproductive/metabolic analyses were performed, as well as ovary and adipose RNA-Seq. These strains varied in PCOS response in a number of key metabolic and reproductive traits, including circulating hormone levels, glucose metabolism, and cardiac function. We applied a linear mixed-effects model to estimate heritability, and genetic (h2), PCOS, and gene-by-PCOS interactions. High h2 was observed for lean and fat mass, glucose, and AUC, whereas PCOS effects were high for the BW change, testosterone, and AUC. Substantial gene-by-PCOS interactions were found for reproductive hormones. Undirected network construction and centrality estimates showed that the reproductive hormones LH and LH/FSH ratio were the strongest central traits connecting metabolic phenotypes. We also showed select strains represent subtypes of human PCOS-metabolism interaction with varied susceptibilities to disease in a PCOS setting. Ovarian RNA-seq analysis of PCOS DEGs showed strong enrichments with human disease settings such as hyperandrogenism, inflammation, and pregnancy hypertension. Similar analyses in GWAT RNA-seq showed enrichments in weight gain, liposarcoma, inflammation, and reproductive diseases were at the top, with adipose genes connecting these diseases and potentially involved with PCOS. In conclusion, we established a PCOS model to study relevant mechanisms intersecting reproduction with metabolism in the context of genetic variation. Presentation: 6/2/2024