Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome

J Clin Endocrinol Metab. 2017 Aug 1;102(8):2862-2872. doi: 10.1210/jc.2017-00612.

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 6 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.

MeSH terms

  • Adult
  • Anti-Mullerian Hormone / genetics*
  • Anti-Mullerian Hormone / metabolism
  • Case-Control Studies
  • Dehydroepiandrosterone Sulfate / metabolism
  • Female
  • Follicle Stimulating Hormone / metabolism
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Luteinizing Hormone / metabolism
  • Polycystic Ovary Syndrome / genetics*
  • Polycystic Ovary Syndrome / metabolism
  • Sex Hormone-Binding Globulin / metabolism
  • Testosterone / metabolism
  • White People / genetics
  • Young Adult

Substances

  • Sex Hormone-Binding Globulin
  • Testosterone
  • Dehydroepiandrosterone Sulfate
  • Anti-Mullerian Hormone
  • Luteinizing Hormone
  • Follicle Stimulating Hormone