Functional Genetic Variation in the Anti-Müllerian Hormone Pathway in Women with Polycystic Ovary Syndrome

Lidija K. Gorsic, Matthew Dapas, Richard S. Legro, M. Geoffrey Hayes, Margrit Urbanek

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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 languageEnglish (US)
Article numberjcem_201802178
Pages (from-to)2855-2874
Number of pages20
JournalJournal of Clinical Endocrinology and Metabolism
Issue number7
StatePublished - Mar 21 2019

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


Dive into the research topics of 'Functional Genetic Variation in the Anti-Müllerian Hormone Pathway in Women with Polycystic Ovary Syndrome'. Together they form a unique fingerprint.

Cite this