rs13394619 — GREB1

Intronic variant in GREB1, an estrogen-responsive gene; the G allele is associated with increased risk of endometriosis, particularly moderate-to-severe disease, across European and East Asian populations

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GREB1 — An Estrogen-Responsive Gene at the Heart of Endometriosis Susceptibility

Endometriosis — tissue similar to the uterine lining growing outside the uterus — affects an estimated 10% of women of reproductive age and accounts for a substantial share of chronic pelvic pain and infertility. The condition is driven by estrogen11 estrogen
estrogen is the primary hormonal fuel for endometriotic lesion growth; ectopic implants express elevated levels of aromatase, generating their own local estrogen supply and sustained by immune tolerance at ectopic implant sites. Roughly half of endometriosis susceptibility is heritable, and rs13394619 in GREB1 is one of the most consistently replicated common genetic risk signals discovered to date.

GREB1 — Growth Regulation by Estrogen in Breast Cancer 1 — was first identified as an early estrogen response gene in breast cancer cell lines. It encodes a nuclear co-factor that physically interacts with hormone receptors to amplify their transcriptional activity. The gene sits on chromosome 2p25.1, and rs13394619 lies in an intronic region between exons 9 and 10 with predicted effects on local splicing activity.

The Mechanism

GREB1 operates as a pan-steroid hormone cofactor22 GREB1 operates as a pan-steroid hormone cofactor
Chadchan et al. Nature Communications, 2024 that behaves differently depending on the hormonal and cellular context. In healthy endometrium during the secretory phase, GREB1 is progesterone-responsive: it physically binds the progesterone receptor and amplifies expression of downstream targets including WNT4 and FOXO1A, which drive the stromal decidualization required for embryo implantation.

In endometriotic lesions the circuit flips. Ectopic tissue accumulates estrogen through locally upregulated aromatase, and in this estrogen-dominant environment GREB1 switches to functioning as an estrogen receptor cofactor — amplifying estrogen-driven gene expression and proliferation of ectopic cells. Mouse models with GREB1 knockout show significantly reduced endometriotic lesion volume and mass. Human endometriotic cells with GREB1 knockdown proliferate more slowly when exposed to estrogen.

The intronic rs13394619 variant may influence how GREB1 is spliced or expressed in endometrial tissue. Although eQTL analyses have not identified a single dramatically altered transcript, fine-mapping studies have identified multiple nearby variants with stronger individual associations, suggesting the region contains regulatory elements relevant to endometrial gene expression. GREB1 mRNA and protein are significantly elevated in peritoneal endometriotic lesions compared with eutopic endometrium from unaffected women33 GREB1 mRNA and protein are significantly elevated in peritoneal endometriotic lesions compared with eutopic endometrium from unaffected women
Pellegrini et al. Fertility and Sterility, 2012, supporting GREB1 as a functionally active contributor to estrogen-dependent lesion growth.

The Evidence

rs13394619 was identified in a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese and European ancestry44 genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese and European ancestry
Nyholt et al. Nature Genetics, 2012. The G allele reached genome-wide significance (OR 1.15, 95% CI 1.09–1.20, P = 6.1 × 10⁻⁸) in the combined analysis, with consistent direction of effect across all contributing cohorts.

A subsequent meta-analysis of eight GWAS datasets encompassing European and Japanese populations55 meta-analysis of eight GWAS datasets encompassing European and Japanese populations
Rahmioglu et al. Human Reproduction Update, 2014 confirmed the association: OR 1.13 (95% CI 1.07–1.20, P = 2.9 × 10⁻⁸). Notably, five of the six confirmed endometriosis loci — including the GREB1 locus — showed stronger effects when restricted to Stage III/IV (moderate-to-severe) disease, with the Stage III/IV enriched estimate for rs13394619 reaching P = 3.5 × 10⁻⁸ and OR = 1.15.

Independent replication in a Belgian cohort of 998 cases and 783 controls66 Belgian cohort of 998 cases and 783 controls
Sapkota et al. Twin Research and Human Genetics, 2015 confirmed nominally significant association, which reached genome-wide significance in the updated meta-analysis. The G allele frequency shows marked ancestry stratification: approximately 0.51 in Europeans and 0.50 in East Asians, but only approximately 0.14 in African populations.

Practical Implications

Carrying G alleles at rs13394619 raises the population-level probability of developing endometriosis, with the greatest estimated effect on moderate-to-severe disease. The absolute risk added by a single common variant of this effect size (OR ~1.13–1.15 per allele) is modest, but the biological pathway — GREB1's estrogen-driven amplification of ectopic tissue growth — points to concrete surveillance and specialist engagement strategies.

The most actionable implication is awareness of cardinal symptoms and willingness to escalate evaluation early. Endometriosis average diagnostic delay remains approximately 7–9 years in many healthcare systems. Severe dysmenorrhea, deep dyspareunia, cyclic bowel or bladder symptoms, and unexplained infertility are the key presentations to act on rather than normalize.

For GG homozygotes — who carry the highest common genetic load at this locus — the elevated probability of moderate-to-severe disease specifically supports proactive fertility counseling, early ovarian reserve assessment, and lower thresholds for specialist referral if symptoms emerge.

Interactions

rs12700667 (7p15.2, near HOXA10/HOXA11): rs12700667 is the other major replicated endometriosis GWAS locus, operating through a distinct candidate pathway — long-range regulation of homeobox genes that orchestrate endometrial development and receptivity. While formal statistical interaction testing between rs13394619 and rs12700667 has not been published, both variants show independent additive genome-wide significant effects on endometriosis risk, both show stronger effects for Stage III/IV disease, and women carrying risk alleles at both loci may represent a subgroup with substantially elevated cumulative susceptibility.

For a supervisor compound action proposal: women carrying the G risk allele at rs13394619 (GG or AG) AND the A risk allele at rs12700667 (AA or AG) carry the two strongest and most replicated common endometriosis GWAS signals simultaneously. The combined recommendation would be: lower threshold for specialist gynecological referral for any pelvic symptoms, earlier baseline ovarian reserve testing (AMH + antral follicle count), and proactive fertility counseling by age 28–30. Evidence level: moderate (both loci independently established; combined effect inferred from consistent additive direction rather than formal interaction analysis).

rs11674184 (GREB1): A second intronic GREB1 variant also associated with endometriosis risk. Studies in Greek populations testing rs11674184 as a proxy for the GREB1 locus found non-significant results in a small cohort, illustrating the population-level heterogeneity in this region. Both variants lie within GREB1 and may tag overlapping haplotypes.

Genotype Interpretations

What each possible genotype means for this variant.

AA No Risk Alleles Normal

No copies of the GREB1 endometriosis risk allele

You carry two copies of the A allele at rs13394619, meaning you do not carry the G risk allele associated with elevated endometriosis susceptibility at this GREB1 locus. Based on global population frequencies, approximately 26% of people share this genotype.

This does not eliminate endometriosis risk — the condition is influenced by many genetic and environmental factors — but you do not carry this particular genetic contribution. The A allele is notably more common in African populations (~86%) than in European (~49%) or East Asian (~50%) populations.

GG Two Risk Alleles High Risk

Two copies of the GREB1 endometriosis risk allele — highest genetic susceptibility at this locus

GREB1 promotes estrogen-dependent proliferation of endometriotic lesions by functioning as an estrogen receptor cofactor in ectopic tissue. Elevated GREB1 expression has been documented in peritoneal endometriotic lesions compared with eutopic endometrium from unaffected controls. GREB1 knockout in mouse endometriosis models significantly reduces lesion volume and mass. The intronic rs13394619 variant may influence GREB1 expression or splicing in endometrial tissue, though the precise mechanism connecting the variant to GREB1 activity has not yet been fully established.

Carrying two G alleles places you at the higher end of the common genetic risk distribution for endometriosis at this locus. rs13394619 was identified across combined European and Japanese GWAS datasets of over 14,000 cases and controls and has been independently replicated in Belgian and other European cohorts. The Stage III/IV enriched analysis reached P = 3.5 × 10⁻⁸ with OR = 1.15 per allele.

For women who have experienced symptoms without diagnosis: average diagnostic delay remains 7–9 years in many healthcare systems, driven by normalization of menstrual pain and the requirement for laparoscopic confirmation. This genetic profile provides additional motivation to pursue early evaluation rather than waiting for pain to escalate.

For women who are asymptomatic: this result is not diagnostic and most GG individuals will not develop clinically significant endometriosis. It is a signal to factor into symptom monitoring and reproductive planning, not a source of alarm.

AG One Risk Allele Carrier

One copy of the GREB1 endometriosis risk allele — modestly elevated susceptibility

GREB1 encodes an estrogen receptor cofactor that amplifies estrogen-driven gene expression. In endometriotic lesions — which generate their own estrogen through locally elevated aromatase — elevated GREB1 promotes ectopic tissue proliferation. The intronic rs13394619 variant may influence GREB1 splicing or expression in endometrial tissue, though the precise molecular mechanism has not been fully resolved.

The risk conferred by heterozygosity at rs13394619 is real but modest on an individual level. Population-based genetic risk estimates inform awareness rather than deterministic prediction. Endometriosis has a prevalence of approximately 10% in reproductive-age women; one G allele may shift that estimate upward modestly, with the greatest estimated effect on surgically confirmed moderate-to-severe disease.

Diagnostic delay for endometriosis averages 7–9 years in many healthcare systems. Recognizing this genetic signal and its associated phenotype may help facilitate earlier evaluation if relevant symptoms develop.