Does the FSHB rs10835638 G allele increase FSH levels in women?

The FSHB gene encodes the beta-subunit of follicle-stimulating hormone (FSH), which dictates the rate-limiting step of functional FSH synthesis. Genetic and molecular evidence robustly demonstrates that the FSHB promoter variant rs10835638 (often designated as c.-211G>T) is a major determinant of circulating FSH levels in women.

Molecular mechanism

• Transcription factor affinity: The G allele at rs10835638 represents the high-expression wild-type allele. It preserves a high-affinity binding site for LIM homeobox 3 (LHX3), a pituitary-specific transcription factor essential for activating FSHB gene expression.
• Transcriptional disruption: The alternative T allele introduces a sequence change that disrupts this LHX3 binding motif, impairing transcription. Because FSH beta-subunit synthesis is the rate-limiting step in mature heterodimeric FSH production, carriers of the G allele (particularly those with the GG genotype) maintain stronger transcriptional activation and subsequently release higher levels of circulating FSH into the bloodstream.

Clinical evidence and endocrine outcomes

• Hormonal phenotype: In premenopausal women, carrying the G allele is strongly associated with higher baseline FSH levels compared to those carrying the T allele.
• Downstream physiological effects: Large-scale genome-wide association studies (GWAS), including analyses from the UK Biobank, demonstrate that the elevated FSH output linked to the G allele manifests in distinct reproductive phenotypes:
  • Menstrual cycle duration: The G allele is associated with shorter menstrual cycles.
  • Age of menopause: It is genetically linked with an earlier onset of natural menopause.
  • Reproductive conditions: The higher gonadotropin exposure associated with the G allele correlates with an increased risk of developing endometriosis.

Bottom line

The FSHB rs10835638 G allele is strongly associated with higher circulating follicle-stimulating hormone levels in women. Mechanistically, this is because the G allele preserves a high-affinity LHX3 transcription factor binding site in the FSHB promoter, maintaining robust transcriptional activation and hormone synthesis.