Abstract
Oocyte loss has a significant impact on fertility and somatic health. Yet, we know little about factors that impact this process. We sought to identify genetic variants associated with ovarian reserve (oocyte number as measured by antral follicle count, AFC). Based on recently published genome-wide scans that identified loci associated with age of menopause, we also sought to test our hypothesis that follicle number and menopausal age share underlying genetic associations. We analyzed menopause-related variants for association with follicle number in an independent population of approximately 450 reproductive-aged women of European and African ancestry; these women were assessed for AFC, anthropometric, clinical, and lifestyle factors. One SNP strongly associated with later menopausal age in Caucasian women (+1.07 ± 0.11 years) in previous work was also associated with higher follicle counts in Caucasians (+2.79 ± 1.67 follicles) in our study. This variant is within the Minichromosome Maintenance Complex Component 8 (MCM8) gene, which we found was expressed within oocytes in follicles of the human ovary. In genome-wide scans of AFC, we also identified one marginally genome-wide and several nominally significant SNPs within several other genes associated with follicle number in both ethnic groups. Further, there were overlapping variants associated with multiple ovarian reserve markers (AFC, serum hormone levels, menopausal age). This study provides the first evidence for direct genetic associations underlying both follicle number and menopause and identifies novel candidate genes. Genetic variants associated with ovarian reserve may facilitate discovery of genetic markers to predict reproductive health and lifespan in women.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-012-1184-0) contains supplementary material, which is available to authorized users.
Highlights
Infertility is remarkably common in humans compared to other species and affects nearly 15 % of reproductive-aged couples (Hull et al 1985; Menken and Larsen 1994; Speroff 2005)
To further analyze the potential association of age at menopause with ovarian reserve, we examined the variants linked with menopausal age for association with several well-known markers of ovarian reserve, including AFC, anti-Mullerian horomone (AMH), and follicle-stimulating hormone (FSH)
We evaluated genetic associations with ovarian reserve and validated variants associated with menopause, in an independent cohort of women directly assessed for follicle number
Summary
Infertility is remarkably common in humans compared to other species and affects nearly 15 % of reproductive-aged couples (Hull et al 1985; Menken and Larsen 1994; Speroff 2005). The number of oocytes increases initially in fetal development and declines, from an established pool, beginning in prenatal life. In development (*3 weeks post-conception), a small population of founder cells, the primordial germ cells (PGCs), migrates to the genital ridges and rapidly proliferates to about 5–7 million germ cells. These PGCs, termed gonocytes, subsequently begin meiosis and differentiate within the developing ovaries (Larsen 1997). Through the process of atresia (cell death), oocyte and follicle loss results in about 1 million follicles within the ovaries at birth (Block 1953). By the time of puberty approximately 500,000 follicles remain, declining to 10,000–50,000 by the late 30s; eventually, the follicle pool is exhausted and menopause ensues (Block 1952, 1953; Faddy et al 1992; Hansen et al 2008; Richardson et al 1987; te Velde and Pearson 2002; te Velde et al 1998)
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