Genetic Regulation of Physiological Reproductive Lifespan and Female Fertility

Abstract

There is substantial genetic variation for common traits associated with reproductive lifespan and for common diseases influencing female fertility. Progress in high-throughput sequencing and genome-wide association studies (GWAS) have transformed our understanding of common genetic risk factors for complex traits and diseases influencing reproductive lifespan and fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. The observations also identify unique genetic risk factors specific to different reproductive diseases impacting on female fertility. Sequencing in patients with primary ovarian insufficiency (POI) have identified mutations in a large number of genes while GWAS have revealed shared genetic risk factors for POI and ovarian ageing. Studies on age at menopause implicate DNA damage/repair genes with implications for follicle health and ageing. In addition to the discovery of individual genes and pathways, the increasingly powerful studies on common genetic risk factors help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits.

Keywords: AMH; FSH; Keywords: reproductive lifespan; fertility; genetic variation; menopause; review.

Figure 1

The location and lead SNP for genetic variants significantly associated with the measured concentrations of key hormones involved in hypothalamic-pituitary regulation of ovarian function. The nearest gene to the lead SNP for each genetic signal is also given.

Figure 2

The location of SNPs significantly associated with reproductive traits and diseases from GWAS studies in the region immediately upstream of the FSHB locus on chromosome 11. The scale at the bottom of the figure is given in kilobases (kb) based on coordinates for human chromosome 11 build hg38. Lead SNPs identified in individual studies are shown below the dotted line and the individual traits and diseases associated with those lead SNPs are listed in the boxes above the line (see Table 3). The four SNPs are all highly correlated and haplotype analysis showing the association of alleles for individual SNPs identified four common allelic combinations or haplotypes with the expected frequencies of each haplotype shown in the circles to the right of each combination.

Figure 3

The application of Mendelian Randomisation to evaluate use of anti-Müllerian hormone (AMH) as a biomarker for ovarian reserve. Genome-wide association studies (GWAS) have identified 56 genetic variants associated with menopause timing [31]. Mendelian Randomisation was used to assess association of menopause timing (a proxy for ovarian reserve) with AMH concentrations [41] making use of the 56 genetic variants associated with age at natural menopause (ANM) to genetically predicted age at menopause. Earlier predicted ANM was associated with higher AMH concentrations supporting the use of AMH to measure ovarian reserve [41].