Pathogenic anti-Müllerian hormone variants in polycystic ovary syndrome

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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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

Fingerprint

Polycystic Ovary Syndrome
Hormones
Steroid 17-alpha-Hydroxylase
Biosynthesis
Androgens
Genes
Genome
Gene encoding
Disease Susceptibility
Luciferases
Gene Frequency
Infertility
Action Potentials
Assays
Outcome Assessment (Health Care)

All Science Journal Classification (ASJC) codes

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

Cite this

Gorsic, L. K., Kosova, G., Werstein, B., Sisk, R., Legro, R., Hayes, M. G., ... 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
Gorsic, Lidija K. ; Kosova, Gulum ; Werstein, Brian ; Sisk, Ryan ; Legro, Richard ; Hayes, M. Geoffrey ; Teixeira, Jose M. ; Dunaif, Andrea ; Urbanek, Margrit. / Pathogenic anti-Müllerian hormone variants in polycystic ovary syndrome. In: Journal of Clinical Endocrinology and Metabolism. 2017 ; Vol. 102, No. 8. pp. 2862-2872.
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Gorsic, LK, Kosova, G, Werstein, B, Sisk, R, Legro, R, Hayes, MG, Teixeira, JM, Dunaif, A & Urbanek, M 2017, 'Pathogenic anti-Müllerian hormone variants in polycystic ovary syndrome', Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 8, pp. 2862-2872. https://doi.org/10.1210/jc.2017-00612

Pathogenic anti-Müllerian hormone variants in polycystic ovary syndrome. / Gorsic, Lidija K.; Kosova, Gulum; Werstein, Brian; Sisk, Ryan; Legro, Richard; Hayes, M. Geoffrey; Teixeira, Jose M.; Dunaif, Andrea; Urbanek, Margrit.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 102, No. 8, 01.08.2017, p. 2862-2872.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pathogenic anti-Müllerian hormone variants in polycystic ovary syndrome

AU - Gorsic, Lidija K.

AU - Kosova, Gulum

AU - Werstein, Brian

AU - Sisk, Ryan

AU - Legro, Richard

AU - Hayes, M. Geoffrey

AU - Teixeira, Jose M.

AU - Dunaif, Andrea

AU - Urbanek, Margrit

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

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