Genes Involved in Initial Follicle Recruitment May Be Associated with Age at Menopause

Context: Timing of menopause is largely influenced by genetic factors. Because menopause occurs when the follicle pool in the ovaries has become exhausted, genes involved in primordial follicle recruitment can be considered as candidate genes for timing of menopause. Objective: The aim was to study the association of 23 tagging single nucleotide polymorphisms in five genes [Anti-Mullerian hormone (AMH), AMH type II receptor (AMHR2), bone morphogenetic protein 15 (BMP15), forkhead transcription factor L2 (FOXL2), and growth differentiation factor-9 (GDF9)] involved in recruitment of the primary follicle pool, including the AMHR2 gene, which has recently been associated with age at menopause. Design: We conducted a cross-sectional association study. Setting and Participants: We studied a population-based sample of 3616 Dutch women with natural menopause. Main Outcome Measure: We measured age at natural menopause. Results: Both studied AMHR2 tagging single nucleotide polymorphisms (rs2002555 and rs11170547) in the AMHR2 gene were associated with age at natural menopause in interaction with parity. Parous rs2002555 G/G carriers had menopause 1 yr later compared with A/A carriers (P = 0.01). For rs11170547, each minor allele (T) was associated with a 0.41-yr later onset of menopause in parous women (P = 0.01). Additionally, rs6521896 in BMP15 was associated with later menopause (beta = 0.41; P = 0.007). Variants in the AMH, FOXL2, and GDF9 genes were not associated with timing of menopause. Conclusions: The present study confirms an earlier finding that variation in the AMHR2 gene modifies the relation between parity and age at natural menopause. In combination with the association of BMP15 with menopausal age, we find that there is evidence that genes involved in primary follicle recruitment influence timing of menopause. (J Clin Endocrinol Metab 96: E473-E479, 2011)