B3581 - Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Children - 24/07/2020

B number: 
Principal applicant name: 
Yee-Ming Chan | Boston Children’s Hospital; Harvard Medical School (USA)
Dr. Joel N. Hirschhorn, Dr. Jia Zhu, Dr. Cecilia Lindgren, Prof. Debbie A. Lawlor, Dr. Abigail Fraser
Title of project: 
Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Children
Proposal summary: 

Polycystic ovarian syndrome (PCOS) is a major health concern that affects up to 10% of reproductive-aged women. This complex, heterogeneous condition is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction. Despite extensive physiologic and genetic studies, the treatment of PCOS remains limited by an incomplete understanding of the pathophysiology of the disorder. Identification of the genetic variants and pathways associated with PCOS susceptibility may provide insights into the pathogenesis of the condition and potential targeted treatments.

We propose to study phenotypes in children that may be associated with PCOS, including obesity, dyslipidemia, and premature adrenarche. Premature adrenarche is a pediatric condition characterized by early production of adrenal androgens such as DHEAS and androstenedione and has been proposed to be a precursor to PCOS in girls. We will calculate a polygenic risk score for PCOS in prepubertal children and test for associations with premature adrenarche and associated cardiometabolic and hyperandrogenic outcomes and biochemical and anthropometric traits. In addition, we will examine these outcomes during the pre-pubertal period in girls who later develop a diagnosis of PCOS in adolescence and young adulthood.

The extension of PCOS genetics to prepubertal children provides the unique opportunity to 1) classify the PCOS pathways into ovarian-dependent factors and nonovarian-dependent factors and 2) characterize the pediatric phenotypes associated with PCOS genetic risk factors, and 3) understand the pre-pubertal manifestations of a future PCOS diagnosis. Overall, investigations in prepubertal children have the potential to provide valuable insights into the mechanisms of pathogenesis and targets for treatment for PCOS.

Impact of research: 
If associations between a polygenic risk score for PCOS and hyperandrogenic and cardiometabolic phenotypes in children are found, the findings would indicate that biological pathways independent of ovarian function contribute to the pathogenesis of PCOS. In contrast, if associations are not identified, it would suggest that ovarian function has a primary causative and/or an essential mediator role in the pathogenesis of PCOS, potentially limited to reproductive-age women. Broadly, this study and future studies will provide insight into the role that genetic risk factors for PCOS play in reproductive and cardiometabolic disease, and how these are shared or distinct between men and women. This study also has the potential to deepen our understanding of pediatric manifestations of genetic risk factors for PCOS, which may inform clinical care and counseling for children with premature adrenarche.
Date proposal received: 
Thursday, 23 July, 2020
Date proposal approved: 
Friday, 24 July, 2020
Endocrinology, Diabetes, Fertility/infertility, Obesity, Computer simulations/modelling/algorithms, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Cardiovascular, Genetics, Sex differences