Project Number: 1R01HD100630-01 Contact PI / Project Leader: URBANEK, MARGRIT
Title: AMH SIGNALING PATHWAY VARIATION IN PCOS Awardee Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Abstract Text:
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-Müllerian 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 (χ2=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 Statement:
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.
Project Terms:
Affect; Age; Amenorrhea; AMHR2 gene; Androgens; Antral; Aromatase; biobank; Bioinformatics; Biological Assay; Biological Markers; Candidate Disease Gene; Catalogs; causal variant; Code; cohort; Complex; CYP11A1 gene; CYP17A1 gene; Data; dehydroepiandrosterone; Development; Disease; disorder risk; Down-Regulation; Electronic Medical Records and Genomics Network; Endocrine; epigenetic variation; Estradiol; Estrone; Etiology; European; Evaluation; Female; folliculogenesis; Follow-Up Studies; Gene Expression Profile; Gene Frequency; General Population; Genes; Genetic; genetic approach; Genetic Databases; Genetic Transcription; genetic variant; Genetic Variation; genome sequencing; Goals; granulosa cell; Growth; Healthcare; Heritability; Heterogeneity; Hormonal; Hormones; Hyperandrogenism; Impairment; improved; in silico; Infertility; innovation; Insulin Resistance; Link; loss of function; Medical center; Medical Records; member; men; Metabolic; Microfluidics; Minor; Missense Mutation; Modeling; Molecular; mRNA Expression; mullerian-inhibiting hormone; Mullerian-inhibiting substance receptor; next generation sequencing; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oligomenorrhea; Ovarian; Ovarian Follicle; Participant; Periodicity; Phenotype; Polycystic Ovary Syndrome; population based; population health; precision medicine; Prevalence; Production; Progesterone; protein expression; receptor; recruit; Regulation; Regulatory Element; Reporting; Reproduction; reproductive; Risk; Role; Signal Transduction; Signaling Protein; Steroid biosynthesis; support network; Syndrome; Testing; Testosterone; theca cell; Tissues; United States National Institutes of Health; Untranslated RNA; Variant; whole genome; Woman
Contact PI Information: Program Official Information: Other PI Information:
Name: URBANEK, MARGRIT
Email: Click to view contact PI email address
Title: ASSISTANT PROFESSOR Name: TAYMANS, SUSAN
Email: Click to view PO email address Not Applicable
Organization: Department / Educational Institution Type: Congressional District:
Name: NORTHWESTERN UNIVERSITY AT CHICAGO
City: CHICAGO Country: UNITED STATES (US) INTERNAL MEDICINE/MEDICINE
SCHOOLS OF MEDICINE State Code: IL
District: 07
Other Information:
FOA: PA-19-056
Study Section: Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Fiscal Year: 2020 Award Notice Date: 28-MAY-2020 DUNS Number: 005436803
Project Start Date: 1-JUN-2020
Budget Start Date: 1-JUN-2020 CFDA Code: 865
Project End Date: 28-FEB-2025
Budget End Date: 28-FEB-2021
Administering Institutes or Centers:
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
Project Funding Information for 2020:
Total Funding: $582,719
Direct Costs: $458,944
Indirect Costs: $123,775
Year Funding IC FY Total Cost by IC
2020 EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT $582,719
History:
Total project funding amount for 1 projects is $582,719*
* Only NIH,CDC,and FDA funding data.
Project Number Sub # Project Title Contact
Principal Investigator Organization FY Admin IC Funding IC FY Total Cost
by IC
1R01HD100630-01 AMH SIGNALING PATHWAY VARIATION IN PCOS URBANEK, MARGRIT NORTHWESTERN UNIVERSITY AT CHICAGO 2020 NICHD
NICHD $582,719
Subprojects:
Project Number Sub # Project Title Contact
Principal Investigator Organization FY Admin IC FY Total Cost
by IC
No Subprojects information available for 1R01HD100630-01
https://projectreporter.nih.gov/project_info_description.cfm?aid=9865636&icde=50955619
