Genetic epistasis in FSH action influences female reproductive lifespan

Genetic factors significantly influence the timing of menarche and menopause, key markers defining the female reproductive lifespan. However, previous genetic studies have primarily focused on additive genetic models, overlooking potential gene-gene interactions ("epistasis"), particularly within critical hormonal pathways such as follicle-stimulating hormone (FSH) signaling. This study investigates epistasis between common genetic variants in the FSH β-subunit gene (FSHB) and the FSH receptor gene (FSHR), by analyzing their combined impact on female reproductive lifespan. Using data from the UK Biobank, we performed genetic association analysis, including 124,336 White British women with reproductive lifespan data and 36,478 with menstrual cycle length data. Participants were stratified according to genotypes at FSHB rs11031006 (G > A) and FSHR rs6166 (C > T), and associations with reproductive lifespan and menstrual cycle length (categorized as <26, 26-28, >28 days) were tested using linear and ordinal logistic regression, including sub-stratified models to assess non-additive (epistatic) effects. In rs11031006 AA homozygotes, rs6166 C allele dosage was associated with longer menstrual cycles (p = 3.79 × 10-2; odds ratio = 1.24) and an extended reproductive lifespan of up to 7 months (p = 3.57 × 10-2). No significant effects were observed in rs11031006 G allele carriers, revealing a genotype-dependent epistatic interaction. By examining variants of the FSH pathway, we demonstrate how subtle changes in hormone production and receptor responsiveness can interact to yield significant biological effects on menstrual cycle dynamics, ovarian aging, and female reproductive lifespan-ultimately highlighting the need to move beyond purely additive genetic models in reproductive genetics.