Abstract:
Background: The gradual decline in oocyte quantity and quality with advancing age ultimately ends in menopause. This process may be accelerated in some women resulting in an earlier age of menopause. As accelerated ovarian ageing exhibits no obvious signs, women who delay pregnancy until later in life may be faced with unexpected fertility issues. Therefore, the ability to accurately predict a woman’s reproductive lifespan is becoming of increasing importance. However current techniques, such as the anti-Mullerian hormone (AMH) test, lack long-term accuracy and predictability. The identification of genetic variants associated with an increased risk of accelerated ovarian ageing may allow for a more accurate and predictive screening tool. Objectives: To investigate whether 37 candidate genetic variants associated with ovarian function, age at natural menopause or early menopause contribute towards an increased risk of low ovarian reserve, as measured by serum AMH level. Methods: This study consisted of 117 cases with low age-specific AMH levels and 128 controls with normal age-specific AMH levels, recruited from Fertility Associates. The 37 variants were genotyped using the Sequenom® MassARRAY iPLEX Gold genotyping system (n=32) and the TaqMan® SNP genotyping assay (n=5). Genotypes and non-genetic factors were assessed for an association with AMH level using statistical association analysis techniques. Results: The rs2384687 (TMEM150B) SNP and the rs1172822/rs2384687 (BRSK1/TMEM150B) haplotype were significantly associated with an increased risk of low ovarian reserve (P-value = 0.0473, OR = 1.4 and P-value = 0.0416, OR = 1.5 respectively). The rs2234693/rs93410799 (ESR1 PvuII/XbaI) haplotype was associated with a decreased risk of low ovarian reserve (P-value = 0.0476, OR = 0.6). Age at menarche and family history also showed significant associations with AMH level (P-value = 0.0095, OR = 1.98 and P-value = 0.0057, OR = 2.4 respectively). Conclusion: From this preliminary study, our results suggest that common variants influencing age at menopause may also modify the risk of accelerated ovarian ageing. Our results extend findings from recent genome-wide association studies and may guide future research efforts in identifying further genetic biomarkers influencing ovarian reserve. These may be incorporated into a genetics-based risk score model to predict a woman’s reproductive lifespan.