Pathogenic anti-Müllerian hormone variants in polycystic ovary syndrome

Lidija K. Gorsic, Gulum Kosova, Brian Werstein, Ryan Sisk, Richard S. Legro, M. Geoffrey Hayes, Jose M. Teixeira, Andrea Dunaif, Margrit Urbanek*

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Context: Polycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility. Objective: Given that common disease-susceptibility variants account for only a small percentage of the estimated PCOS heritability, we tested the hypothesis that rare variants contribute to this deficit in heritability. Design, Setting, and Participants: Unbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control subjects identified potentially deleterious variants in AMH, the gene encoding anti-Müllerian hormone (AMH). Targeted sequencing of AMH of 643 patients with PCOS and 153 control patients was used to replicate WGS findings. Main Outcome Measures: Dual luciferase reporter assays measured the impact of the variants on downstream AMH signaling. Results: We found 24 rare (minor allele frequency < 0.01) AMH variants in patients with PCOS and control subjects; 18 variants were specific to women with PCOS. Seventeen of 18 (94%) PCOS-specific variants had significantly reduced AMH signaling, whereas none of ± variants observed in control subjects showed significant defects in signaling. Thus, we identified rare AMH coding variants that reduced AMH-mediated signaling in a subset of patients with PCOS. Conclusion: To our knowledge, this study is the first to identify rare genetic variants associated with a common PCOS phenotype. Our findings suggest decreased AMH signaling as a mechanism for the pathogenesis of PCOS. AMH decreases androgen biosynthesis by inhibiting CYP17 activity; a potential mechanism of action for AMH variants in PCOS, therefore, is to increase androgen biosynthesis due to decreased AMH-mediated inhibition of CYP17 activity.

Original languageEnglish (US)
Pages (from-to)2862-2872
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number8
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

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

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    Gorsic, L. K., Kosova, G., Werstein, B., Sisk, R., Legro, R. S., Hayes, M. G., Teixeira, J. M., Dunaif, A., & Urbanek, M. (2017). Pathogenic anti-Müllerian hormone variants in polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 102(8), 2862-2872. https://doi.org/10.1210/jc.2017-00612