Genomic Markers of Ovarian Reserve

Abstract

Ovarian reserve and its utilization, over a reproductive life span, are determined by genetic, epigenetic, and environmental factors. The establishment of the primordial follicle pool and the rate of primordial follicle activation have been under intense study to determine genetic factors that affect reproductive lifespan. Much has been learned from transgenic animal models about the developmental origins of the primordial follicle pool and mechanisms that lead to primordial follicle activation, folliculogenesis, and the maturation of a single oocyte with each menstrual cycle. Recent genome-wide association studies on the age of human menopause have identified approximately 20 loci, and shown the importance of factors involved in double-strand break repair and immunology. Studies to date from animal models and humans show that many genes determine ovarian aging, and that there is no single dominant allele yet responsible for depletion of the ovarian reserve. Personalized genomic approaches will need to take into account the high degree of genetic heterogeneity, family pedigree, and functional data of the genes critical at various stages of ovarian development to predict women's reproductive life span.

Dynamics of the Ovarian Reserve and Impact of Genetic and Epidemiological Factors on Age of Menopause1

“…--substantially overlapping the list assembled by Wood and Rajkovic [86], who also summarize substantial effects of many of the candidate genes in mice. Instead, the GWAS hits were startlingly different from the candidate gene list.…”

“…As in other GWAS studies, the DNA variants revealed explained only part (up to 4.1%) of the variance of age of menopause in the populations studied. Nevertheless, their importance is increased by confirmatory GWAS findings in other ethnic groups (reviewed by [86]). Furthermore, other sources of variation, like the FRAXA expansion and FRAXE microdeletions, were not assessed and analyses taking into account insertion/deletions and rare alleles and looking at larger cohorts will certainly explicate more of the genetic contribution to the timing of reproductive lifespan.…”

ABO blood type is associated with ovarian reserve in Chinese women with subfertility

“…The nuclear receptor 5A1 (NR5A1) and transforming growth factor β receptor (TGFBR1) genes, which are located on chromosome 9q34 and 9q22 near the ABO locus, are related to ovarian function. Therefore, recombination may occur between these genes and the ABO type genes at a relatively high rate, which would increase the likelihood of these genes being inherited together with ABO [19, 20]. Additionally, variation in genes as phased haplotypes might affect the folding and levels of other proteins and thus increase the chances of inheriting specific allele combinations together [21, 22].…”

Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability

“…Women with POF present with amenorrhea (primary or secondary) and hypoestrogenic symptoms (i.e., hot flashes, vaginal dryness, premature osteoporosis). POF is genetically heterogeneous (2), with few genes identified, and can be idiopathic and nonsyndromic or part of a genetic syndrome.…”