rs4944653 — PRSS23 PRSS23 Ovarian Serine Protease

An intergenic tag SNP ~50 kb downstream of PRSS23 (serine protease 23) on chromosome 11q14.2; the G allele is associated with higher serum FSH levels in a dose-responsive pattern (AA 9.0, AG 9.5, GG 10.7 IU/L) and with PCOS susceptibility, reflecting PRSS23's role in granulosa cell survival and follicular atresia

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PRSS23 — When a Follicle Culling Enzyme Receives Too Much Encouragement

Every menstrual cycle, hundreds of follicles begin to grow but only one (occasionally two) is selected to ovulate. The rest undergo programmed destruction — a process called follicular atresia11 follicular atresia
the apoptotic elimination of follicles that fail the selection process; accelerated atresia reduces ovarian reserve and is implicated in PCOS, diminished ovarian reserve, and early menopause — and the rate at which this culling occurs determines how rapidly the ovarian reserve depletes over a woman's reproductive lifespan. PRSS2322 PRSS23
serine protease 23; a conserved trypsin- family endopeptidase expressed in granulosa cells, theca tissue, and atretic follicles; located at chromosome 11q14.2 is one of the enzymes that carries out this culling. The rs4944653-G variant, located approximately 50 kilobases downstream of the PRSS23 gene, tags a regulatory signal that amplifies PRSS23 activity — and the consequences show up in measurable changes in circulating FSH.

The Mechanism

PRSS23 is expressed primarily in granulosa cells of secondary and early antral follicles — the very cells responsible for producing estrogen and expressing FSH receptor (FSHR). A 2026 study in avian granulosa cells33 A 2026 study in avian granulosa cells
Wang et al. PRSS23 Promotes Ovarian Follicular Atresia in Wuding Chickens by Coordinately Suppressing Steroidogenesis and PI3K/AKT/mTOR Survival Signaling. Genes (Basel), 2026 showed that PRSS23 overexpression simultaneously downregulates FSHR and the steroidogenic enzymes CYP19A1, StAR, and HSD3β1, while activating the mitochondrial apoptotic pathway (increasing BAX, decreasing BCL2) via PI3K/AKT/mTOR inhibition. The result is cell cycle arrest and granulosa cell death — the molecular signature of atresia.

Critically, PRSS23 expression is downregulated by gonadotropins near the time of ovulation, 44 Wahlberg et al. Expression and localization of the serine proteases HtrA1, SP23, and SP35 in the mouse ovary. Endocrinology, 2008 suggesting FSH normally suppresses this atretic enzyme to protect dominant follicles. When the rs4944653-G allele increases PRSS23 expression in the follicular microenvironment, the pituitary must compensate by producing more FSH to overcome amplified atretic pressure — hence the higher serum FSH seen in G carriers.

The Evidence

The clearest human evidence comes from Tidwell et al. 202455 Tidwell et al. 2024
Phenotypes Associated With Polycystic Ovary Syndrome Risk Variants. J Endocr Soc, 2024, a study of 404 PCOS cases and 408 controls from the Utah PCOS cohort. The rs4944653-G allele showed a strict dose-response relationship with FSH levels: AA carriers averaged 9.0 ± 3.1 IU/L, AG carriers 9.5 ± 3.2 IU/L, and GG homozygotes 10.7 ± 4.6 IU/L. The association survived adjustment for both age (beta 0.040 ± 0.010, P<.001) and BMI (beta 0.041 ± 0.010, P<.001), confirming it is not mediated by obesity — a key distinction in a PCOS population.

The PRSS23 locus was also among the loci associated with gonadotropin levels in this study, alongside the well-established FSHB locus. The G allele is common: approximately 62% of women globally are GG homozygotes, and a further 33% are AG heterozygotes, meaning fewer than 5% of women carry the AA (lowest-FSH) genotype.

The broader PCOS genetic architecture was established by the Day et al. 2018 meta-analysis66 Day et al. 2018 meta-analysis
Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genetics, 2018, which identified 14 genome-wide significant loci across 10,074 cases and 103,164 European-ancestry controls. PRSS23-region variants sit within this PCOS risk landscape, providing the biological rationale for the FSH association: elevated FSH in the absence of ovarian failure may reflect a continuous push against increased follicular atresia at the granulosa cell level.

Practical Actions

For women with one or two copies of the G allele, the elevated FSH signal has two actionable implications. First, standard FSH thresholds used to assess ovarian reserve (the commonly used "normal < 10 IU/L" cut-off) may need to be contextualised genetically — a GG woman with FSH of 10.5 IU/L may be within her genotype-normal range rather than showing early diminished ovarian reserve. Second, women with GG genotype and PCOS should discuss whether their FSH level is primarily driven by genetic background or by PCOS- related gonadotropin dysregulation, as this distinction affects treatment decisions.

Anti-Müllerian hormone (AMH) — which reflects the number of remaining antral follicles and is not directly influenced by this PRSS23 variant — provides a complementary measure of ovarian reserve that is unconfounded by this genetic background FSH elevation.

Interactions

The rs4944653 PRSS23 variant acts through the FSH axis and thus interacts conceptually with variants in the FSHB gene (rs11031006, which directly encodes the FSH beta subunit) and with ovarian reserve variants such as HELQ rs12651246. A woman carrying both elevated- FSH PRSS23 genotype and a FSHB variant would be expected to show compounded gonadotropin dysregulation, though direct interaction studies have not yet been published.

The PCOS susceptibility locus ZBTB16 (rs1784692) and the PRSS23 locus both appear in the Tidwell et al. 2024 study, and while they affect different PCOS phenotypic features (ovarian morphology vs. FSH levels respectively), women carrying risk alleles at both loci may present with a more complete PCOS endocrine profile.

Genotype Interpretations

What each possible genotype means for this variant.

AA Low Atretic Drive Normal

Lowest FSH baseline — ovarian reserve signalling within typical range

You carry two copies of the A allele at the PRSS23 locus, which is associated with the lowest FSH levels in published studies (average 9.0 ± 3.1 IU/L in the Tidwell et al. cohort). This genotype is uncommon — fewer than 5% of women globally carry AA — and reflects a relatively lower level of PRSS23-driven follicular atresia signalling. Your FSH levels are less likely to be inflated by this particular genetic background, which means standard FSH reference ranges apply to you without a genotype-specific adjustment.

AG Intermediate Atretic Drive Intermediate

Modestly elevated FSH — one copy of the risk allele

Heterozygous G carriers sit in an intermediate position: somewhat more atretic drive than AA women, but less than GG homozygotes. The effect is modest — roughly half an IU/L above the AA baseline — and clinically meaningful mainly in the context of FSH interpretation and PCOS risk assessment. In women being evaluated for fertility or ovarian reserve, an FSH in the 9–10 IU/L range may reflect this genetic background rather than early follicular depletion. Anti-Müllerian hormone (AMH) and antral follicle count are more direct measures of actual reserve and are not influenced by this variant.

GG High Atretic Drive High Risk

Elevated FSH baseline — two copies of the PRSS23 risk allele

PRSS23 is expressed in granulosa cells — the cells that surround and nourish developing follicles — and drives follicular atresia (programmed follicle death). When PRSS23 activity is elevated, more follicles undergo atresia rather than reaching the dominant selection stage, and the pituitary compensates by secreting more FSH to sustain follicle recruitment. The result is a chronically elevated FSH baseline that is a property of your genetic makeup rather than a sign of depleted ovarian reserve per se.

This distinction matters clinically: an FSH of 10–11 IU/L in a GG woman may be her "normal," whereas the same value in an AA woman would be more anomalous. AMH and antral follicle count (AFC) — which reflect actual follicle numbers — are not influenced by this variant and should be the primary ovarian reserve metrics for GG carriers. In the PCOS context, an elevated PRSS23-driven FSH may also contribute to the LH:FSH ratio patterns seen in some PCOS phenotypes.