Ovarian Physiology and GWAS: Biobanks, Biology, and Beyond

Abstract

Ovarian function is central to female fertility, and several genome-wide association studies (GWAS) have been carried out to elucidate the genetic background of traits and disorders that reflect and affect ovarian physiology. While GWAS have been successful in reporting numerous genetic associations and highlighting involved pathways relevant to reproductive aging, for ovarian disorders, such as premature ovarian insufficiency and polycystic ovary syndrome, research has lagged behind due to insufficient study sample size. Novel approaches to study design and analysis methods that help to fit GWAS findings into biological context will improve our knowledge about genetics governing ovarian function in fertility and disease, and provide input for clinical tools and better patient management.

Keywords: menopause; ovarian reserve; polycystic ovary syndrome; premature ovarian insufficiency.

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How To Fit the GWAS Findings in a Larger Biological Picture? Various approaches (A) contextualizing GWAS findings, and (B) harnessing GWAS findings for translational output.

Figure 1. Ovarian Reserve Throughout Life, Normal Ovarian Function, And the Impact of Various Pathologies.

The ovarian reserve is established before birth, and thereafter the number of follicles containing the oocytes decreases through controlled atresia until menopause when the ovarian reserve is virtually exhausted. Normally, during the reproductive lifespan ovarian follicles go through distinct developmental stages and one oocyte is released monthly. However, in women with polycystic ovary syndrome (PCOS), hormonal disturbances result in follicular arrest and anovulation, while in premature ovarian insufficiency (POI) the ovarian reserve is depleted prematurely. During ovarian stimulation (COS) used for in vitro fertilization (IVF), exogenous hormones are used to stimulate the growth and release of several oocytes.

Figure 2. Reported Genetic Associations and Genetic Correlations between Phenotypes.

(A) Genome-wide significant loci associated with menarche, menopause, polycystic ovary syndrome, FSH and LH levels, and menstrual cycle length; and genes associated with monogenic forms of POI. (B) Genetic correlations between phenotypes reflecting ovarian physiology and overall health status. Data are from published studies [9,10,19] that report genetic correlations based on observed pleiotropy between loci or LD score regression analysis. Abbreviations: AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; LD, linkage disequilibrium; LH, luteinizing hormone; PAI-1, plasminogen activator inhibitor type 1; PCOS, polycystic ovary syndrome; POI, premature ovarian insufficiency.