rs10093345 — EIF4EBP1 EIF4EBP1 rs10093345

Intergenic GWAS locus near EIF4EBP1 (encoding the mTOR translation repressor 4E-BP1) where the T allele is associated with modestly lower circulating anti-Müllerian hormone (AMH), a key biomarker of ovarian reserve and fertility timing

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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.

Genotype Interpretations

What each possible genotype means for this variant.

CC Higher AMH Genotype Beneficial

Both alleles favor higher AMH levels at this locus

You carry two copies of the C allele at rs10093345. In the GWAS meta-analysis of 9,668 pre-menopausal women, each T allele is associated with approximately 0.08 unit lower AMH — so the CC genotype, free of any T alleles, is associated with relatively higher AMH at this locus compared to CT or TT. About 11% of people of European descent share this genotype, while it is more common in East Asian populations (~27%).

AMH is influenced by many factors beyond genetics, including age, body composition, and lifestyle. This result reflects one genetic contributor to the broader picture.

CT Intermediate AMH Genotype Intermediate

One T allele — modest genetic influence toward slightly lower AMH

The T allele at rs10093345 is the more common allele in European (73%), South Asian (76%), and Latino (~69%) populations, meaning the CT genotype is the modal outcome in these populations. The effect size in the GWAS (beta = 0.08, 95% CI 0.06–0.10) is statistically robust but modest in clinical terms.

Where this becomes relevant is in women who are already at the margins of ovarian reserve — for example, approaching age 35–37 when AMH typically begins to decline more steeply, or with a personal history of ovarian surgery, autoimmune conditions, or chemotherapy that may have already reduced reserve. In those contexts, knowing about a genetic tendency toward lower AMH adds value to an already active fertility evaluation conversation.

TT Lower AMH Genotype Decreased

Two T alleles — genetic tendency toward modestly reduced AMH levels

The EIF4EBP1 locus reached genome-wide significance at P = 1 × 10⁻⁹ in a meta-analysis of 9,668 women — a well-powered study — confirming this is a real, replicated genetic association. The T allele effect direction was consistent across the component cohorts. However, the effect per allele (beta 0.08) must be interpreted in context: AMH levels span roughly 0.1 to >10 ng/mL across reproductive-age women, and a 0.08-unit shift on the transformed scale used in GWAS corresponds to a relatively small absolute change in most women's range.

Where TT genotype matters most is in younger women who have any independent reason to be concerned about ovarian reserve — either because AMH testing has already shown lower-than-expected values, or because they have had ovarian surgery, a history of autoimmune disease, family history of early menopause, or a planned delay of childbearing beyond age 35–38. The mTOR/EIF4EBP1 pathway involvement is also mechanistically relevant for primordial follicle activation: dysregulation of mTORC1 signaling in granulosa cells can accelerate follicle pool depletion, though whether this SNP's regulatory effect reaches clinical significance in most carriers remains to be established by follow-up functional studies.

The EIF4EBP1 locus colocalizes with a local eQTL for the gene, suggesting the T allele alters EIF4EBP1 expression in tissues relevant to AMH secretion. This mechanistic coherence strengthens confidence in the association beyond statistical significance alone.