rs7986407 — FOXO1

Intronic variant in FOXO1, a pro-apoptotic transcription factor whose suppression by the AKT/progestin pathway promotes uterine fibroid cell survival; the G allele is associated with elevated uterine leiomyoma risk in multiple GWAS, while the A allele associates with later age at natural menopause.

See your personal result for FOXO1

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

FOXO1 rs7986407 — The Apoptosis Switch in Uterine Fibroid Cells

Uterine fibroids (leiomyomata) affect up to 70% of women by age 50 and are the leading indication for hysterectomy worldwide. Their growth depends on a fundamental imbalance: fibroid smooth muscle cells proliferate but resist dying. FOXO1 — forkhead box protein O111 forkhead box protein O1
a transcription factor that drives expression of pro-apoptotic genes including BIM, PUMA, and Fas ligand — is a central regulator of that life-or-death balance. An intronic variant in FOXO1, rs7986407, has emerged from multiple genome-wide association studies as a locus influencing both uterine leiomyoma risk and the timing of natural menopause, two phenotypes that converge on estrogen exposure duration and uterine smooth muscle cell biology.

The Mechanism

Under normal conditions, FOXO1 translocates to the nucleus and transcribes genes that initiate programmed cell death — a key brake on abnormal cell accumulation. In leiomyoma cells, however, progestins (which drive fibroid growth) rapidly activate the PI3K/AKT signaling cascade22 PI3K/AKT signaling cascade
a pro-survival kinase pathway that is constitutively elevated in many tumors. Activated AKT phosphorylates FOXO1 at Ser256, causing it to be sequestered in the cytoplasm where it cannot reach its target genes. The result: pro-death signals are silenced and fibroid cells survive and accumulate. This mechanism was directly demonstrated by Hoekstra et al. (2009), who showed that blocking AKT or forcing nuclear FOXO1 entry with Psammaplysene A restored apoptosis in leiomyoma cells33 blocking AKT or forcing nuclear FOXO1 entry with Psammaplysene A restored apoptosis in leiomyoma cells
Hoekstra AV et al. J Clin Endocrinol Metab 2009.

The rs7986407 variant is intronic and does not alter the FOXO1 protein sequence. Its functional effect likely operates through regulatory mechanisms — altered splicing efficiency, changes in intronic enhancer activity, or linkage disequilibrium with regulatory variants in the FOXO1 locus — that may modulate FOXO1 expression levels or transcript stability in uterine smooth muscle cells. The precise molecular consequence of the G allele in this tissue remains an open research question.

FOXO1 also plays a broader role in reproductive physiology: in ovarian granulosa cells, FOXO1 and its close family member FOXO3 regulate follicular development and granulosa cell apoptosis. Selective deletion of both in mice caused complete infertility44 caused complete infertility
Liu Z et al. Mol Endocrinol 2015, demonstrating that FOXO-family transcription factors are essential throughout the reproductive axis, not only in the uterus.

The Evidence

The locus around rs7986407 has been identified in multiple large-scale GWAS efforts. The GWAS Catalog reports two fibroid associations at this variant: one with OR 1.07 (95% CI 1.04–1.10; p = 7 × 10⁻⁸; risk allele G) from studies in European-ancestry women, and a second association in a larger meta-analysis (p = 2 × 10⁻¹³; beta 0.064) where the A allele direction diverges — reflecting the complexities of phenotypic stratification across studies. A third entry in the GWAS Catalog records an association with uterine leiomyoma specifically (OR 0.93 per A allele; p = 2 × 10⁻¹⁸), consistent with a protective role of the A allele on fibroid risk.

The same A allele is associated with later age at natural menopause55 later age at natural menopause
later menopause means longer total estrogen exposure across the reproductive lifespan at genome-wide significance (p = 4 × 10⁻¹⁹), suggesting that the A allele promotes prolonged functional ovarian activity. The relationship between these two A-allele phenotypes (later menopause and reduced fibroid risk, or context-dependent fibroid association) likely reflects the complex role of estrogen timing in uterine tissue biology.

Practical Actions

For women carrying two G alleles at rs7986407, the evidence may suggest a modest but biologically grounded susceptibility to uterine fibroid development.

Early pelvic ultrasound surveillance is the most actionable monitoring step for GG carriers. If fibroids are identified, awareness of the AKT/FOXO1 pathway biology may be relevant to treatment considerations, particularly given ongoing research into AKT-targeted fibroid therapies.

Genotype Interpretations

What each possible genotype means for this variant.

AA Lower-Risk Genotype Normal

Common genotype — may be associated with reduced fibroid susceptibility

In the GWAS Catalog, the A allele of rs7986407 is associated with a modest protective direction for uterine leiomyoma. The same allele also associates with later age at natural menopause (p = 4 × 10⁻¹⁹), though the mechanistic link between these two phenotypes is not fully established.

The A/A genotype is not risk-free for fibroid development — fibroids arise from a complex interplay of genetic, hormonal, and environmental factors, and this single SNP explains only a small portion of population variance. However, based on available GWAS evidence, this genotype does not confer the elevated susceptibility signal associated with the G allele.

AG Intermediate Risk Intermediate

One copy of the risk allele — modestly elevated fibroid susceptibility possible

Under an additive model, the heterozygous AG genotype may carry approximately half the fibroid susceptibility signal associated with GG homozygosity. The original GWAS-catalog entry for the G-risk association reports OR 1.07 (95% CI 1.04–1.10, p = 7 × 10⁻⁸) per allele from a large European-ancestry cohort, suggesting that each G allele provides a roughly 7% relative increase in odds, placing AG carriers modestly above baseline.

GG Higher-Risk Genotype High Risk

Two copies of the risk allele — elevated uterine fibroid susceptibility suggested by GWAS data

Under an additive GWAS model, GG homozygotes at rs7986407 carry approximately twice the allelic fibroid risk associated with one G allele. The GWAS Catalog records genome-wide significant associations at this variant with uterine fibroids (p = 7 × 10⁻⁸, OR ~1.07 per G allele) and uterine leiomyoma (p = 2 × 10⁻¹³ to 2 × 10⁻¹⁸ across studies).

Under normal conditions, FOXO1 translocates to the nucleus and activates BIM, PUMA, and Fas ligand — genes that initiate programmed cell death in abnormal cells. Progestins (which drive fibroid growth) activate AKT, which phosphorylates FOXO1 at Ser256 and traps it in the cytoplasm. Restoring nuclear FOXO1 (via AKT inhibition or Psammaplysene A treatment) induced apoptosis in leiomyoma cells in vitro [Hoekstra et al. 2009, PMID 19240153].

The A-allele association with later natural menopause (p = 4 × 10⁻¹⁹) suggests that FOXO1 activity in the ovary also influences reproductive lifespan; GG carriers at rs7986407 may have a somewhat shorter window of natural estrogen protection, adding complexity to the overall reproductive phenotype.