rs3820282 — WNT4

Intronic variant in WNT4 on chromosome 1p36.12 that introduces a high-affinity estrogen receptor alpha binding site, upregulating WNT4 in endometrial stromal cells; the T allele is associated with increased endometriosis and uterine fibroid risk through enhanced stromal invasibility, while the C allele associates with pelvic organ prolapse risk — an example of antagonistic pleiotropy in reproductive tissue biology

See your personal result for WNT4

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

WNT4 rs3820282 — The Estrogen-Responsive Molecular Switch in the Uterine Lining

Endometriosis — in which tissue resembling the uterine lining grows outside the uterus — affects approximately 10% of women of reproductive age and is one of the leading causes of chronic pelvic pain and infertility. The condition is strongly heritable, yet the molecular events that allow retrograde endometrial cells to implant and survive on peritoneal surfaces remain incompletely understood. rs3820282 stands out among endometriosis risk variants because functional experiments have revealed its mechanism with unusual clarity: it creates a new binding site for the estrogen receptor11 creates a new binding site for the estrogen receptor
ESR1: estrogen receptor alpha, a transcription factor that mediates the downstream effects of estrogen on gene expression directly within the first intron of WNT4, converting what was a transcriptionally quiet region into an estrogen-responsive switch.

rs3820282 lies on chromosome 1p36.12 within intron 1 of the WNT4 gene, approximately 21 kb from the widely-studied rs7521902. Although both SNPs tag the same 1p36 haplotype block and are in linkage disequilibrium22 linkage disequilibrium
LD: the tendency for nearby variants to be inherited together; variants in high LD are often proxies for the same underlying causal signal in European populations, rs3820282 has emerged from fine-mapping studies as the more direct molecular actor — the variant whose alternative allele appears to alter the DNA sequence itself rather than simply tagging a nearby causal change.

The Mechanism

WNT4 encodes a secreted glycoprotein belonging to the Wnt signaling family, which is essential for the embryonic development of the female reproductive tract from Müllerian duct precursors and for the monthly decidualization of the endometrium. The protein operates downstream of the IHH–COUPTFII pathway33 IHH–COUPTFII pathway
the Indian Hedgehog – COUP transcription factor II axis, which coordinates progesterone response in endometrial stromal cells during the secretory phase to drive the transformation of endometrial stromal cells into specialized decidual cells — a prerequisite for embryo implantation.

The T allele at rs3820282 changes the intronic sequence from C to T, introducing a high-affinity recognition motif for estrogen receptor alpha (ERα). When estrogen levels peak before ovulation, ERα bound to this newly created site activates WNT4 transcription in the endometrial stroma, producing 1.48–3.27 log2-fold higher WNT4 expression44 1.48–3.27 log2-fold higher WNT4 expression
measured in CRISPR-edited knock-in mouse lines carrying the human T allele; Pavličev et al. 2024 Nature Communications during the proestrus and estrus cycle phases. The downstream effect is a uterine stromal environment with enhanced invasibility — better at accepting an implanting embryo, but also more permissive to attachment by ectopic endometrial fragments shed into the peritoneal cavity during retrograde menstruation.

This same variant simultaneously acts as an expression quantitative trait locus (eQTL)55 expression quantitative trait locus (eQTL)
a variant that affects how much RNA is produced from a nearby gene rather than changing the protein sequence for two nearby genes: LINC00339 (a long non-coding RNA, whose expression is decreased by the risk allele) and CDC42 (a Rho GTPase involved in cytoskeletal organization and cell migration, whose expression is increased). Elevated CDC42 activity may further facilitate the migratory behavior of ectopic endometrial cells.

The Evidence

Fine-mapping of the chromosome 1p36 WNT4 region in 930 endometriosis cases and 959 controls66 930 endometriosis cases and 959 controls
Luong et al. Int J Mol Epidemiol Genet, 2013 identified rs3820282 as one of three variants with stronger association than the previously-reported rs7521902, noting its position within recognition motifs for both ESR1 and ESR2 — a direct prediction of the estrogen-receptor mechanism later confirmed experimentally.

In a 7,090-person fine-mapping study77 7,090-person fine-mapping study
Powell et al. Human Molecular Genetics, 2016 (2,594 endometriosis cases, 4,496 controls), rs3820282 showed the strongest association at the 1p36.12 locus for endometriosis (P = 1.84 × 10⁻⁵, OR = 1.244, 95% CI 1.126–1.375), outperforming rs7521902 as a direct disease signal. The same variant was confirmed as an eQTL for both LINC00339 and CDC42 in endometrial tissue.

The functional confirmation arrived in 2024: CRISPR knock-in experiments88 CRISPR knock-in experiments
Pavličev et al. Nature Communications, 2024 in mice introduced the human T allele into the equivalent Wnt4 locus. Both independently generated knock-in lines showed significantly higher uterine Wnt4 expression compared to wildtype animals during the estrogen-peak phases (proestrus and estrus), confirming the estrogen-receptor-binding mechanism proposed from human sequence analysis.

A striking feature of rs3820282 is antagonistic pleiotropy across reproductive tissues. The same T allele that raises endometriosis and fibroid risk appears to confer reproductive benefit: across multiple GWAS, the T allele is associated with longer gestation and reduced preterm birth risk. Conversely, the C allele — which is relatively rare in East Asian populations — is the risk allele for pelvic organ prolapse99 pelvic organ prolapse
a condition in which the pelvic floor structures weaken and pelvic organs descend into the vaginal canal (OR 1.18, P = 3 × 10⁻²¹). This explains why the T allele has remained common despite its association with endometriosis: in evolutionary terms, the same molecular mechanism that facilitates embryo implantation comes at the cost of ectopic endometrial invasion.

Practical Implications

For women carrying one or two copies of the T allele, the most actionable implication is awareness of endometriosis symptoms and a lower threshold for seeking specialist evaluation rather than accepting menstrual pain as normal. The average diagnostic delay for endometriosis is 4–11 years from first symptoms, driven by normalization of dysmenorrhea and the requirement for laparoscopic confirmation.

The WNT4 locus is also associated with uterine fibroids (leiomyomas) at genome-wide significance. T allele carriers may therefore warrant gynecological evaluation that includes assessment for both conditions — a pelvic ultrasound can screen for both ovarian endometriomas and uterine fibroid burden simultaneously.

No supplement or dietary intervention specifically targeting the estrogen-receptor-WNT4 axis has been studied. Progestin-based hormonal therapies remain the mainstay of endometriosis management and address the progesterone-resistance pathway through which WNT4 dysregulation is thought to act.

Interactions

rs7521902 (WNT4 1p36.12 sentinel): rs7521902 is in moderate-to-high linkage disequilibrium with rs3820282 in European populations, meaning both variants partly tag the same underlying haplotype signal. In populations where LD is lower (East Asian, Brazilian cohorts), rs3820282 may be the more informative marker. Users carrying risk alleles at both loci reflect the same biological signal rather than independent additive contributions.

rs4762326 (VEZT, chromosome 12q23.2): The VEZT locus encodes vezatin, a component of adherens junctions that mediates cell-cell adhesion. VEZT and WNT4 represent two mechanistically distinct pathways to ectopic endometrial implantation — cell adhesion capacity vs. estrogen-driven stromal invasibility. Carrying risk alleles at both loci could compound endometriosis susceptibility through complementary mechanisms, though formal gene-gene interaction data have not been published.

rs1250248 (FN1 — fibronectin 1): An epistatic interaction between the WNT4 locus (rs7521902) and FN1 has been described for ovarian endometriosis (OR 1.56 for the interaction term; Pagliardini et al. 2013, PMID 23142796). Fibronectin is a major extracellular matrix glycoprotein that works alongside cell adhesion receptors; it may interact directly with the WNT4-driven stromal invasibility that rs3820282 mediates.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

Common protective genotype — no WNT4 estrogen-response risk allele

You carry two copies of the C (reference) allele at rs3820282. This is the common genotype globally, carried by approximately 74% of people. At this locus, the C allele is the reference allele and confers typical endometriosis and uterine fibroid risk from the WNT4 1p36.12 region.

Interestingly, the C allele at this position is itself associated with slightly elevated pelvic organ prolapse risk (OR 1.18 in GWAS data), while the T allele carries the endometriosis and fibroid signal. This antagonistic relationship means neither allele is uniformly "protective."

CT One Risk Allele Intermediate

One copy of the WNT4 estrogen-response risk allele — modestly elevated endometriosis and fibroid susceptibility

Fine-mapping of the 1p36.12 WNT4 region identified rs3820282 as the strongest single association signal for endometriosis at this locus (OR 1.244 per allele, P = 1.84×10⁻⁵; Powell et al. 2016 PMID 28171565), outperforming the more widely-cited rs7521902 in direct comparisons. The T allele functions as an eQTL that increases CDC42 expression and decreases LINC00339 expression in endometrial tissue, with CDC42 upregulation potentially facilitating the migratory behavior of ectopic endometrial cells.

Functional CRISPR mouse studies published in 2024 (Pavličev et al. Nature Communications PMID 38346980) confirmed that the human T allele drives 1.5–3.3 fold higher WNT4 expression in uterine stroma during the estrogen-peak phase, validating the mechanistic hypothesis and establishing this as one of the few endometriosis GWAS variants with direct molecular proof of function.

The actionable implication for heterozygous carriers is heightened awareness of endometriosis and fibroid symptoms rather than alarm — this is a common, moderate-effect risk variant. The biggest yield comes from not normalizing relevant symptoms and seeking specialist evaluation promptly.

TT Two Risk Alleles High Risk

Two copies of the WNT4 estrogen-response risk allele — elevated endometriosis and fibroid susceptibility at this locus

The rs3820282 T allele is the most functionally characterized endometriosis risk variant at the WNT4 1p36.12 locus. Its mechanism — creation of a high-affinity ESR1 binding site that drives estrogen-responsive WNT4 expression in endometrial stroma — makes biological sense for endometriosis pathogenesis: elevated stromal WNT4 activity during the estrogen peak primes the uterine environment for invasibility, facilitating both embryo implantation and, inadvertently, ectopic endometrial cell attachment.

The same elevated WNT4 signaling that confers this benefit appears to simultaneously increase uterine fibroid risk (T allele: beta +0.15, P = 6×10⁻⁸⁷ in the largest fibroid GWAS; OR ~1.16 per allele in the leiomyomata GWAS). TT homozygotes therefore face elevated susceptibility at two common uterine conditions — endometriosis and fibroids — through the same molecular mechanism.

Conversely, the same T allele associates with longer gestation and reduced preterm birth risk — an example of antagonistic pleiotropy where the same variant has been maintained at appreciable frequency because it confers reproductive benefit alongside disease risk. This trade-off is particularly evident in East Asian populations, where the T allele is the major allele (frequency ~50%) and TT homozygosity is common.

The WNT4 locus also shows pleiotropy with epithelial ovarian cancer (T allele: OR ~1.11–1.12 for serous subtype), reinforcing the role of elevated WNT4 activity in gynecological tissue oncogenesis.

TT homozygosity is a signal worth factoring into fertility planning discussions and annual gynecological surveillance — not a source of alarm, since most TT carriers will not develop clinically significant endometriosis or fibroids, but a genuine reason to seek evaluation earlier rather than later when symptoms arise.