rs10093345 — EIF4EBP1 EIF4EBP1 rs10093345

EIF4EBP1 and AMH — A Common Variant That Nudges Ovarian Reserve Downward

Anti-Müllerian hormone (AMH) is a small protein secreted exclusively by the granulosa cells of growing ovarian follicles. Because it reflects the pool of actively developing follicles, circulating AMH levels serve as the most practical and cycle-stable biomarker of ovarian reserve¹¹ ovarian reserve
The remaining functional pool of oocytes — the eggs available for future ovulation. Ovarian reserve declines continuously and irreversibly with age; AMH is the earliest and most sensitive blood marker of that decline. Genetic variation explains a meaningful fraction of why two women of the same age can have AMH levels that differ by an order of magnitude. rs10093345 is among the variants contributing to that heritable spread.

The Mechanism

rs10093345 lies on chromosome 8 (8p11.23) in an intergenic region near the EIF4EBP1 gene²² EIF4EBP1 gene
Eukaryotic translation initiation factor 4E binding protein 1 — encodes 4E-BP1, a repressor protein that blocks the assembly of the cap-dependent translation initiation complex by binding eIF4E. 4E-BP1 is one of the principal downstream effectors of the mTORC1³³ mTORC1
mechanistic target of rapamycin complex 1 — a central integrator of nutrient, growth factor, and energy signals that controls whether cells are in an anabolic (building) or catabolic (breaking-down) state signaling axis: when mTORC1 is active, it phosphorylates and inactivates 4E-BP1, releasing eIF4E to drive cap-dependent protein synthesis. When mTORC1 is suppressed, 4E-BP1 acts as a brake on translation.

In the ovary, mTOR signaling plays a critical role in granulosa cell proliferation and follicular activation. Glycolysis-driven mTOR activation in granulosa cells is a key trigger for primordial follicle recruitment⁴⁴ Glycolysis-driven mTOR activation in granulosa cells is a key trigger for primordial follicle recruitment
Zhang et al. Cell Death & Disease, 2022 (PMID 35087042); dysregulation of this pathway can accelerate follicle depletion or impair granulosa cell function. Colocalization analysis in the Pujol-Gualdo 2024 GWAS confirmed that the rs10093345 signal colocalizes with an expression quantitative trait locus (eQTL) for EIF4EBP1 itself — meaning the risk allele likely alters EIF4EBP1 transcript levels in relevant tissues, subtly modifying translational output in granulosa cells and potentially the quantity or timing of AMH secretion. The exact regulatory mechanism (enhancer, promoter, or splicing effect) has not yet been resolved at the molecular level.

The Evidence

The rs10093345 association was identified in a genome-wide association meta-analysis of AMH in 9,668 pre-menopausal women (ages 15–48)⁵⁵ genome-wide association meta-analysis of AMH in 9,668 pre-menopausal women (ages 15–48)
Pujol-Gualdo et al. Human Reproduction, 2024. Combined data from the Northern Finland Birth Cohort 1966 (n = 2,619) with a prior AMH GWAS meta-analysis (n = 7,049). The EIF4EBP1 locus reached genome-wide significance (P = 1 × 10⁻⁹) with a beta of 0.08 AMH units per T allele (95% CI 0.06–0.10), meaning each T allele is associated with approximately 0.08 unit lower AMH on the scale used in the analysis. The locus was one of three novel discoveries in this study, alongside CHEK2 and BMP4.

The effect is modest per allele — not large enough to determine AMH reserve on its own. Given the T allele frequency of approximately 73% in Europeans, the TT genotype is in fact the most common genotype in that population (~53% of individuals), meaning the "risk" genotype here describes the majority. Clinical AMH variability is dominated by age and individual biology; rs10093345 represents a small probabilistic shift in the distribution, rather than a deterministic outcome.

AMH peaks in the early 20s and declines progressively toward menopause⁶⁶ AMH peaks in the early 20s and declines progressively toward menopause
Dewailly et al. Human Reproduction Update, 2014 (PMID 24430863). Its correlation with antral follicle count makes it useful for individualized FSH dosing in IVF, for identifying women at risk of poor ovarian response, and for early detection of premature ovarian insufficiency (POI). In young women, very low AMH is a clinically meaningful signal for increased POI risk⁷⁷ very low AMH is a clinically meaningful signal for increased POI risk
Nelson et al. Climacteric, 2023 (PMID 36651193), and this genetic variant nudges baseline AMH in that direction — modestly and probabilistically, not absolutely.

Practical Actions

For TT homozygotes: the practical implication is awareness that your baseline AMH may trend slightly lower than the population average attributable to this locus — which is reason to consider an AMH measurement as part of any fertility evaluation, particularly before age 35 when reserve is still expected to be adequate and a documented baseline is most informative. For women considering delayed childbearing, knowing your AMH trend can inform the timing and urgency of fertility planning decisions, including whether egg freezing is worth discussing while reserve is still favorable.

For CT heterozygotes: the effect is approximately half that of TT homozygosity and is less clinically significant in isolation. An AMH test remains informative if fertility planning is actively relevant to you.

Interactions

This locus was identified in the same study that confirmed associations at MCM8 (rs16991615 — involved in DNA repair during follicular development), AMH itself (the gene encoding the hormone), and TEX41. Women carrying risk alleles at multiple AMH-influencing loci may have a compounded effect on circulating levels, though formal polygenic interaction analysis across these loci has not been published. The broader genetic architecture of ovarian reserve is emerging, with several GWAS loci converging on granulosa cell biology and follicular development pathways.