Polycystic Ovary Syndrome (PCOS) is a complex disorder with endocrine, reproductive, and metabolic features. With a prevalence of 5-15%, it is the most common form of infertility in reproductive age women. Women with PCOS are also at increased risk of developing obesity, insulin resistance and Type 2 Diabetes. Consequently, PCOS has a strong negative impact on the health of the population contributing >$5 billion to the healthcare burden in the US annually. It is characterized by elevated testosterone levels, irregular periods, and polycystic ovaries. Although PCOS is highly heritable, traditional genetic approaches have identified <5% of all the genetic variation contributing to this syndrome. Rare genetic variants and regulatory element variation may account for this ?missing? heritability. In an unbiased whole genome sequencing screen of women with PCOS, we identified missense mutations in the anti-Mllerian hormone gene (AMH). AMH is strong candidate gene for PCOS. It is critical to two central features of PCOS: ovarian follicle recruitment and development and androgen production. AMH is elevated in PCOS and has been proposed as a biomarker for PCOS. In follow-up studies, we identified a total of 37 rare coding and regulatory variants in AMH and its type 2 receptor (AMHR2). These variants had significantly reduced signaling capacity in 6.7% of our cohort. No variants with impaired activity were observed in controls and no variants with increased signaling activity were observed in PCOS or reproductively normal womrn. Our results are highly significant relative to reproductively normal women (?2=18.0, p=2.20E-05) and to non-Finnish European population-based controls (p < 10-8). Our findings are the first identification of functionally validated variants for PCOS and provide strong evidence for a critical role of the AMH signaling cascade in PCOS. However, to date we have only comprehensibly screened AMH and its receptor AMH. Given that most genes are believed to impact disease risk through highly connected cellular networks, it is our overarching hypothesis that other members of the AMH signaling cascade are also impaired in PCOS To ascertain which components of the AMH signaling cascade are impaired in PCOS and how they impact PCOS subphenotypes, we will apply innovative, state-of-the-art genetic, molecular, and bioinformatic approaches. We will create a comprehensive catalog of putative causal variants in ~30 members of the AMH signaling cascade in multiethnic PCOS cohort and determined the functional consequences of these variants in PCOS and the general population. Collectively, these studies will be the first comprehensive evaluation of functional genetic variation of this critical signaling cascade in PCOS, ii. elucidate the role of members of the AMH signaling cascade in PCOS and female reproduction in general, and iii. define the molecular mechanisms that underlie phenotypic heterogeneity of PCOS identifying PCOS subtypes leading to improved treatment options. These studies are thus a critical step towards the successful implementation of Precision Medicine in the context of PCOS and female reproduction.

Public Health Relevance

Polycystic ovary syndrome (PCOS) is the most common form of annovulatory infertility of reproductive age women affecting 5-10% of reproductive age women and contributing >$5 billion to the healthcare burden in the US annually. We have identified functional variants in the AMH and AMHR2 genes that are very strongly associated with PCOS and identify a PCOS sub-phenotypic. The goal of this proposal is to identify the function of PCOS causal variants in the broader AMH signaling pathway which will explain the molecular basis and phenotypic heterogeneity of PCOS and the successful implementation of Precision Medicine.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Taymans, Susan
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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