Abstract
Polycystic ovary syndrome (PCOS) is a highly heritable, common endocrine disorder characterized by hyperandrogenism, irregular menses, and polycystic ovaries. PCOS is often accompanied by elevated levels of anti-Mu llerian hormone (AMH). AMH inhibits follicle maturation. AMH also inhibits steroidogenesis through transcriptional repression of CYP17A1. We recently identified 16 rare PCOS-specific pathogenic variants in AMH. Objective: To test whether additional members of the AMH signaling pathway also contribute to the etiology of PCOS. Participants/Design: Targeted resequencing of coding and regulatory regions of AMH and its specific type 2 receptor, AMHR2, was performed on 608 women affected with PCOS and 142 reproductively normal control women. Prediction tools of deleteriousness and in silico evidence of epigenetic modification were used to prioritize variants for functional evaluation. Dual-luciferase reporter assays and splicing assays were used to measure the impact of genetic variants on function. Results: We identified 20 additional variants in/near AMH and AMHR2 with significantly reduced signaling activity in in vitro assays. Collectively, from our previous study and as reported herein, we have identified a total of 37 variants with impaired activity in/near AMH and AMHR2 in 41 women affected with PCOS, or 6.7% of our PCOS cohort. Furthermore, no functional variants were observed in the 142 phenotyped controls. The functional variants were significantly associated with PCOS in our cohort of 608 women with PCOS and 142 controls (P = 2.3 3 1025) and very strongly associated with PCOS relative to a larger non-Finnish European (gnomAD) population-based control cohort (P , 1 3 1029).
Original language | English (US) |
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Article number | jcem_201802178 |
Pages (from-to) | 2855-2874 |
Number of pages | 20 |
Journal | Journal of clinical endocrinology and metabolism |
Volume | 104 |
Issue number | 7 |
DOIs | |
State | Published - Mar 21 2019 |
Funding
Financial Support: This work was supported by National Institutes of Health Grants R01 HD057450 (M.U.), P50 HD044405 (M.U), R01 HD056510 (R.S.L.), T32 DK007196 (LKG), and T32 DK007196 (MD). Partial funding for the clinical studies was provided by Grants UL1 TR000150, UL1 RR033184, UL1 TR000430, and UL1 RR025758 from the National Center for Advancing Translational Sciences. Some hormone assays were performed at the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core that is supported by Grant U54 HD28934 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
ASJC Scopus subject areas
- Biochemistry, medical
- Endocrinology
- Biochemistry
- Clinical Biochemistry
- Endocrinology, Diabetes and Metabolism