Dataset Information

Pathogenic Anti-Mullerian Hormone Variants in Polycystic Ovary Syndrome.

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.

SUBMITTER: Gorsic LK

PROVIDER: S-EPMC5546867 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome.

Gorsic Lidija K LK Kosova Gulum G Werstein Brian B Sisk Ryan R Legro Richard S RS Hayes M Geoffrey MG Teixeira Jose M JM Dunaif Andrea A Urbanek Margrit M

The Journal of clinical endocrinology and metabolism 20170801 8

<h4>Context</h4>Polycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility.<h4>Objective</h4>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.<h4>Design, setting, and participants</h4>Unbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control su ...[more]

PMID: 28505284

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Project description:BackgroundThe majority of available studies on the AMH thresholds were not age-specific and performed the receiver operating characteristic curve (ROC) analysis, based on variations in sensitivity and specificity rather than positive and negative predictive values (PPV and NPV, respectively), which are more clinically applicable. Moreover, all of these studies used a pre-specified age categorization to report the age-specific cut-off values of AMH.MethodsA total of 803 women, including 303 PCOS patients and 500 eumenorrheic non-hirsute control women, were enrolled in the present study. The PCOS group included PCOS women, aged 20-40 years, who were referred to the Reproductive Endocrinology Research Center, Tehran, Iran. The Rotterdam consensus criteria were used for diagnosis of PCOS. The control group was selected among women, aged 20-40 years, who participated in Tehran Lipid and Glucose cohort Study (TLGS). Generalized additive models (GAMs) were used to identify the optimal cut-off points for various age categories. The cut-off levels of AMH in different age categories were estimated, using the Bayesian method.Main results and the role of chanceTwo optimal cut-off levels of AMH (ng/ml) were identified at the age of 27 and 35 years, based on GAMs. The cut-off levels for the prediction of PCOS in the age categories of 20-27, 27-35, and 35-40 years were 5.7 (95 % CI: 5.48-6.19), 4.55 (95 % CI: 4.52-4.64), and 3.72 (95 % CI: 3.55-3.80), respectively. Based on the Bayesian method, the PPV and NPV of these cut-off levels were as follows: PPV = 0.98 (95 % CI: 0.96-0.99) and NPV = 0.40 (95 % CI: 0.30-0.51) for the age group of 20-27 years; PPV = 0.96 (95 % CI: 0.91-0.99) and NPV = 0.82 (95 % CI: 0.78-0.86) for the age group of 27-35 years; and PPV = 0.86 (95 % CI: 0.80-0.94) and NPV = 0.96 (95 % CI: 0.93-0.98) for the age group of 35-40 years.ConclusionsApplication of age-specific cut-off levels of AMH, according to the GAMs and Bayesian method, could elegantly assess the value of AMH in discriminating PCOS patients in all age categories.