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

Research output: Contribution to journalArticle

15 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, Lidija K. ; Kosova, Gulum ; Werstein, Brian ; Sisk, Ryan ; Legro, Richard S. ; 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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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-M{\"u}llerian 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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Gorsic, LK, Kosova, G, Werstein, B, Sisk, R, Legro, RS, 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 S.; 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 S.

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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