rs73625113 — ESR1 ESR1 rs73625113

An intronic regulatory variant in ESR1 at the 6q25.1 locus identified as a high-confidence causal endometriosis SNP (posterior inclusion probability 0.506) through fine-mapping of the Rahmioglu et al. 2023 mega-GWAS; the T allele lies in strong LD with eQTLs driving ESR1 expression and DNA methylation near ESR1, implicating altered estrogen receptor signaling in endometriosis susceptibility and pain subphenotypes including dysmenorrhea and dyspareunia

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ESR1 rs73625113 — Estrogen Receptor Signaling at the 6q25.1 Endometriosis Locus

The ESR1 gene encodes estrogen receptor alpha (ERα)11 estrogen receptor alpha (ERα)
the primary nuclear receptor through which estradiol controls gene transcription in reproductive tissues; ERα-driven signaling is essential for endometrial proliferation and implantation, and its dysregulation is central to endometriosis pathogenesis, the most pharmacologically targeted protein in endometriosis management. Endometriosis affects roughly 1 in 10 women of reproductive age — causing pelvic pain, dysmenorrhea, dyspareunia, and infertility — and estrogen is essential for the growth and persistence of ectopic lesions. Variants that shift ERα expression or activity are therefore credible contributors to disease susceptibility.

rs73625113 sits in an intronic region of ESR1 at chromosome 6q25.1 and was identified as a high-confidence causal variant at this locus through Bayesian fine-mapping, with a posterior inclusion probability (π) of 0.506 — meaning the statistical evidence assigns approximately a 50% probability that this specific variant, rather than a neighboring tag SNP, is the functional change driving the association signal. It is one of only a small number of variants genome-wide that reached this level of fine-mapping resolution in endometriosis genetics.

The Mechanism

The T allele at rs73625113 does not alter the ESR1 protein sequence — it lies in a non-coding intronic region. Its biological effect operates through gene regulation. Fine-mapping analyses show that rs73625113 is in strong linkage disequilibrium (r² > 0.8) with rs294173922 rs2941739
a nearby variant identified as an expression quantitative trait locus (eQTL) for ESR1 in blood tissue; eQTLs are variants that alter the amount of mRNA produced from a gene, and with multiple methylation quantitative trait loci (mQTLs) at CpG sites near ESR1. Together, this evidence points to rs73625113 marking a regulatory region that influences ESR1 transcription and local chromatin methylation.

ESR1 expression in endometrial tissue governs the proliferative response to estradiol across the menstrual cycle. When ERα signaling is constitutively elevated or dysregulated — as altered ESR1 eQTLs would predict — endometrial stromal cells become hypersensitive to estrogen, potentially facilitating ectopic implantation and lesion maintenance. ESR1 also regulates expression of COMT (catechol-O-methyltransferase), a key enzyme in the catabolism of pain-relevant catecholamine neurotransmitters including dopamine and epinephrine; this secondary pathway may explain why the 6q25.1 locus is particularly enriched for pain subphenotypes beyond what pure lesion burden would predict.

The Evidence

The 6q25.1 ESR1 locus was first established as genome-wide significant for endometriosis in the Sapkota et al. 2017 GWAS meta-analysis33 Sapkota et al. 2017 GWAS meta-analysis
17,045 cases and 191,596 controls; 5 novel loci identified: FN1, CCDC170/ESR1, SYNE1, FSHB; together explaining up to 5.19% of disease variance. The locus houses multiple genes — CCDC170, ESR1, and SYNE1 — and the 2017 analysis could not distinguish which was the primary causal gene.

The Rahmioglu et al. 2023 mega-GWAS44 Rahmioglu et al. 2023 mega-GWAS
60,674 cases and 701,926 controls of predominantly European ancestry; 42 genome-wide significant loci comprising 49 distinct signals; fine-mapping using Bayesian credible sets; significant genetic correlations with 11 pain conditions including migraine and multisite chronic pain resolved this ambiguity. Through Bayesian fine-mapping, rs73625113 (intronic to ESR1) emerged with π=0.506 as a high-confidence causal candidate distinct from the neighboring SYNE1 variant rs71575922 (π=0.997). This indicates the 6q25.1 locus harbors at least two independent functional variants — one in SYNE1 and one in ESR1 — each contributing to the overall association signal through different biological mechanisms.

The pain subphenotype analyses in the 2023 study revealed striking effect size enrichment: while the 6q25.1 locus overall shows a modest OR for endometriosis diagnosis, the pain-specific signals are substantially larger — dysmenorrhea OR 1.49, dyspareunia OR 1.48, severe dyspareunia OR 2.07, and acyclical pelvic pain OR 1.44. This pattern supports a model in which the ESR1 regulatory variant contributes to pain amplification — partly through direct estrogenic effects on nociceptive pathways, and partly through the downstream COMT pathway governing catecholamine catabolism.

Practical Actions

Carrying the T allele at rs73625113 is most clinically meaningful as a pain-risk signal in endometriosis. Women with endometriosis who carry T may be predisposed to more severe dysmenorrhea and dyspareunia than the lesion burden alone would predict, because the ESR1/COMT regulatory pathway shapes how the nervous system processes pelvic nociception. Monitoring pain subphenotypes separately from lesion staging and discussing estrogen-modulating interventions with a gynecologist familiar with this mechanism are the most actionable responses to this result.

For those who have not yet received an endometriosis diagnosis: a T-allele result in this gene does not diagnose the condition, but it supports a lower threshold for seeking specialist evaluation of pelvic pain symptoms rather than normalizing dysmenorrhea. The average diagnostic delay for endometriosis remains 4–11 years from symptom onset.

Interactions

rs71575922 (SYNE1, 6q25.1): This SNP is co-located at the same GWAS locus but represents a distinct fine-mapped signal (π=0.997 for SYNE1 vs. π=0.506 for ESR1 at rs73625113). Women carrying risk alleles at both variants carry the full genetic burden of the 6q25.1 locus — both the neuromechemical (SYNE1/Nesprin-1) and estrogen receptor (ESR1) pathways converge on pain amplification at this locus.

Supervisor compound action proposal: women carrying both the rs71575922 G allele (SYNE1) and the rs73625113 T allele (ESR1) represent the highest genetic burden at the 6q25.1 locus, with two independently fine-mapped signals both enriched for pain subphenotypes. Proposed combined recommendation: integrated pain management addressing both neuromuscular dysfunction (pelvic floor PT, neuromodulation) and estrogen-signaling contributions (tracking cycle-linked vs. cycle-independent pain, discussion with specialist about estrogen-lowering hormonal options). Evidence level: moderate (both loci independently established; combined effect inferred from locus biology, not directly studied).

rs12700667 (HOXA cluster, 7p15.2): A second major endometriosis GWAS locus; the HOXA cluster regulates endometrial receptivity and Müllerian development, suggesting a complementary mechanism (lesion biology/stromal invasion) that may act additively with the ESR1 pain-pathway signal at this locus.

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal

No ESR1 rs73625113 risk allele — standard estrogen receptor signaling at this locus

You carry two G alleles at rs73625113, the reference allele at this ESR1 intronic site. This is the most common genotype globally, present in approximately 93% of people. You do not carry the T allele that fine-mapping studies have identified as a high-confidence causal variant for endometriosis risk and pain subphenotype susceptibility at the 6q25.1 locus.

This does not eliminate endometriosis risk — the condition is polygenic and influenced by many other loci and non-genetic factors. Symptoms consistent with endometriosis warrant clinical evaluation regardless of this result.

TT ESR1 Homozygous Risk High Risk

Two copies of the ESR1 endometriosis risk allele — highest genetic load at this regulatory locus

TT homozygosity is rare enough (~0.1%) that individual outcome data are scarce and most findings are extrapolated from per-allele additive models. The practical interpretation is that this genotype carries the maximum ESR1 regulatory load from this locus.

The ESR1 locus at 6q25.1 represents one of the clearest genomic examples of an endometriosis variant whose effect is most pronounced in the pain-dominant rather than the asymptomatic-lesion-dominant endometriosis subtype. This has treatment implications: surgical management targeting lesions may be less effective at controlling pain for carriers of this allele than for women where the pain is primarily lesion-driven, because the estrogen receptor regulatory pathway contributes independently to nociceptive amplification.

The ESR1 gene also regulates COMT expression. COMT metabolizes catecholamines including dopamine in pain processing pathways. Higher ESR1 expression (predicted by the T allele eQTL at this locus) may suppress COMT, slowing catecholamine catabolism and sustaining noradrenergic pain signaling — a mechanism complementary to the peripheral estrogen-driven lesion biology of endometriosis.

For TT carriers, the combination of early specialist evaluation, systematic pain subtype monitoring, and discussion of estrogen-suppressive management options provides the most targeted response to the underlying biology.

GT ESR1 Risk Allele Carrier Carrier

One copy of the ESR1 endometriosis risk allele — modestly elevated pain subphenotype susceptibility

Fine-mapping of the endometriosis GWAS 6q25.1 locus identified rs73625113 as a high-confidence causal variant with posterior inclusion probability (π) of 0.506, meaning statistical evidence assigns approximately 50% probability that this specific variant (rather than a neighboring tag SNP) is the functional change. This level of fine-mapping resolution is unusual for a GWAS locus and gives the result stronger causal credibility than a typical association SNP.

The mechanism operates through ESR1 expression regulation rather than protein alteration. ESR1 encodes estrogen receptor alpha — the primary receptor through which estradiol controls endometrial proliferation, immune tolerance in the uterus, and indirectly, COMT-mediated catecholamine catabolism. COMT governs dopamine and epinephrine breakdown in pain pathways, and its regulation by ESR1 provides a plausible link between this estrogen receptor variant and amplified pelvic pain sensitivity beyond what lesion burden alone would predict.

For T-allele carriers who have endometriosis, the pain subphenotype signal suggests that estrogen-mediated mechanisms — not only anatomical lesion extent — may drive pain severity. This has practical implications for treatment: progesterone-based or GnRH-based hormonal management that suppresses estrogen signaling may be particularly relevant for pain control in T carriers, beyond its use for lesion suppression.