Leveraging human genomics to discover mechanisms underlying ovarian insufficiency across the female reproductive lifecourse

Ovarian insufficiency, affecting more than 3% of women globally, compromises the entire endocrine function and fertility potential of the ovary with significant clinical, psychological, and socioeconomic implications. Primary ovarian insufficiency (POI, ovarian function cessation before 40 years) usually presents in adulthood but, in 10%, is severe and early-onset (EO-POI, before 25 years). Previously, I have demonstrated that both polygenic and monogenic mechanisms likely contribute to POI. However, their contributions across the phenotypic spectrum are unknown, and mechanistic understandings of POI and other ovarian insufficiency phenotypes are very limited. Accordingly, clinical management largely amounts to hormone replacement therapy after end-stage ovarian failure has already occurred. I now plan to a) combine gene discovery in unique clinical POI cohorts with population genetics approaches, both with greatly enlarged scale, to elucidate the genetic architecture of POI and identify novel genetic mechanisms of ovarian insufficiency phenotypes, and b) use functional in vitro cellular models to illuminate the roles of two novel ovarian insufficiency genes/pathways as key regulators of human ovarian function: the canonical estrogen receptor ESR2 and the TGFβ/activin receptor TGFBR1. This work will advance our mechanistic understanding of POI, improve the clinical management of ovarian insufficiency, and answer fundamental questions in ovarian biology.