rs2268361 — FSHR FSHR Intronic Variant (c.669-5590)

Intronic variant in the FSHR gene associated with PCOS susceptibility and FSH level modulation; the C allele tags a GWAS-identified risk haplotype that elevates basal FSH and increases PCOS risk, while the T allele is protective and associated with normal FSH levels

Moderate Risk Factor Share

Details

Gene: FSHR
Chromosome: 2
Risk allele: C
Clinical: Risk Factor
Evidence: Moderate

Population Frequency

16%

48%

36%

External

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FSHR rs2268361 — The Intronic Risk Tag That Modulates FSH Sensitivity and PCOS Risk

The follicle-stimulating hormone receptor gene (FSHR) harbors three well-studied variants that influence reproductive outcomes: the two missense variants rs6165 (Ala307Thr) and rs6166 (Asn680Ser) in the coding region, and this intronic variant rs2268361, located 5,590 bases upstream of exon 7 within intron 6 NM_000145.4:c.669-5590G>T¹¹ NM_000145.4:c.669-5590G>T
Transcriptional notation on the minus strand; the variant is C>T on the plus (genome file) strand. While it does not change the FSHR protein sequence, rs2268361 was independently identified as a PCOS risk locus in genome-wide association studies of Han Chinese women and subsequently replicated across European and other ancestries. The C allele tags a haplotype associated with elevated basal FSH and increased PCOS susceptibility; the T allele is protective and associated with normal FSH levels.

The Mechanism

As an intronic variant, rs2268361 does not alter any amino acid in the FSH receptor protein. Its functional effect is presumed to be regulatory — affecting how much FSHR mRNA is produced or how it is processed²² regulatory — affecting how much FSHR mRNA is produced or how it is processed
Intronic variants can act as splicing regulators, transcription factor binding sites, or LD tags for nearby functional elements. The precise molecular mechanism has not been established in published functional studies as of 2026. The most parsimonious interpretation is that rs2268361 tags a regulatory haplotype that subtly reduces FSHR expression or alters splicing efficiency in granulosa cells, leading downstream to compensatory pituitary FSH secretion and modestly altered FSH receptor signaling in the ovary.

Importantly, this locus is distinct from the rs6165/rs6166 haplotype. While rs6165 and rs6166 are in near-complete linkage disequilibrium with each other (r²>0.80), rs2268361 represents an independent signal at the FSHR locus³³ an independent signal at the FSHR locus
The Shi et al. 2012 GWAS specifically identified this as a second independent signal at 2p16.3, separate from the coding-variant haplotype. This means rs2268361 may carry additional predictive information even in individuals already genotyped for rs6165 and rs6166.

The Evidence

The clearest functional evidence comes from a cross-ethnic replication study of 2,718 women⁴⁴ cross-ethnic replication study of 2,718 women
Saxena et al., Human Reproduction 2015 that tested 11 Han Chinese GWAS PCOS variants in European ancestry cohorts (Boston discovery: 485 PCOS cases, 407 controls; Greece: 884 cases, 311 controls; Boston EMR: 350 cases, 1,258 controls). Of the 11 variants tested, rs2268361-T was the clearest replicating signal: OR 0.84 (95% CI 0.76–0.93, P=0.002) for PCOS protection, and a significant reduction in FSH concentrations in T carriers (beta=-0.15 ± 0.05, P=0.0029 in standardized units). The FSH-lowering effect of the T allele aligns with the PCOS-protective effect: less FSH stimulation (or more efficient receptor response) reduces the hormonal milieu that promotes PCOS pathophysiology.

A large meta-analysis of 47 case-control studies⁵⁵ large meta-analysis of 47 case-control studies
Sharma et al., Metabolic Syndrome and Related Disorders 2023 covering 10,584 PCOS cases and 16,150 controls confirmed the protective direction of effect: OR 0.84 (95% CI 0.78–0.89) for the T allele (or equivalently, the C allele confers risk at OR ~1.19–1.28). This consistency across 47 studies spanning multiple ethnicities places the association on firm epidemiological ground, though the functional mechanism remains incompletely characterized.

Not all individual studies replicate the finding. A Chinese case-control study of 400 PCOS women and 480 controls⁶⁶ Chinese case-control study of 400 PCOS women and 480 controls
Zhang et al., Journal of Assisted Reproduction and Genetics 2021 did not find a significant association for rs2268361 in isolation, though rs6166 (the coding variant) showed significant effects. This heterogeneity across populations is expected for an intronic regulatory variant whose effect may depend on local linkage patterns and population history.

A Saudi Arabian case-control study⁷⁷ Saudi Arabian case-control study
Alharbi et al., BMC Endocrine Disorders 2019 observed that homozygous TT genotype at rs2268361 was associated with normal AMH levels among non-PCOS women, suggesting the TT genotype is associated with a preserved ovarian reserve signal in healthy controls. While this was a small study (95 PCOS cases, 94 controls), it aligns with the biological model of T allele maintaining appropriate FSH-receptor axis sensitivity.

Epistatic studies add additional nuance. A Colombian PCOS cohort study⁸⁸ A Colombian PCOS cohort study
Bernal-Hernández et al., Genes 2024 identified rs2268361 as part of the best-fit three-locus synergistic interaction model (P<0.0001), paired with two other FSHR/TOX3 variants. This suggests that the independent additive effect of rs2268361 is amplified in specific genetic backgrounds.

Practical Implications

For most individuals carrying one or two C alleles, the practical implications are subtle rather than deterministic. The variant modulates PCOS susceptibility at a population level (shifting OR by ~19%) but does not define individual outcome. Its main clinical relevance lies in two areas:

Basal FSH interpretation: The C allele tracks with modestly elevated FSH levels even in non-PCOS women. Women with CC or CT genotypes who have elevated day-3 FSH should have this contextualized alongside AMH — the FSHR rs2268361 C allele may contribute a small upward push to basal FSH independent of ovarian reserve.

PCOS context: In women already diagnosed with or suspected of PCOS, carrying the CC genotype adds to the overall genetic burden at the FSHR locus. Combined with the rs6165/rs6166 haplotype status, a full FSHR genotype picture (three variants) gives the most complete assessment of FSHR-axis function.

Interactions

rs6166 (FSHR Asn680Ser) and rs6165 (FSHR Ala307Thr): rs2268361 represents an independent genetic signal at the FSHR locus. Unlike the near-complete LD between rs6165 and rs6166 (r²>0.80), rs2268361 is not captured by the coding-variant haplotype. Individuals heterozygous at rs2268361 (CT) who are also homozygous for the coding-variant risk haplotype (CC at rs6165, GG at rs6166) carry risk signals from two independent FSHR mechanisms — the regulatory/intronic effect (rs2268361) and the protein-level sensitivity changes (rs6165/rs6166). The combined FSHR genetic burden has not been formally quantified in a single integrated model.

rs1394205 (FSHR promoter, -29G>A): The FSHR promoter variant rs1394205 also operates at the expression level rather than protein sequence. The relationship between rs2268361 and rs1394205 LD is not well characterized in published literature; they may operate through different regulatory elements on the same gene.

Genotype Interpretations

What each possible genotype means for this variant:

TT “Protective Homozygote” Normal

Two protective T alleles — normal FSHR regulatory function and lower PCOS risk

You carry two copies of the T allele at rs2268361, the common protective genotype at this intronic FSHR locus. About 36% of the general population globally shares this genotype (higher in Europeans at approximately 41%, lower in African populations at approximately 9%). This genotype is associated with normal basal FSH levels and reduced risk of polycystic ovary syndrome compared to C allele carriers.

The T allele tags an FSHR regulatory haplotype associated with appropriate FSH receptor axis sensitivity. Studies show TT women tend to have normal AMH levels and normal FSH concentrations, consistent with a well-calibrated hypothalamic-pituitary-ovarian axis.

CT “Intermediate Risk” Intermediate Caution

One C and one T allele — modestly elevated PCOS risk and mildly higher FSH tendency

The additive effect of rs2268361 means CT carriers sit between TT and CC on the FSH sensitivity spectrum. Cross-ethnic replication data show the T allele lowers FSH concentrations by approximately 0.15 standard deviations per allele dose (Saxena et al. 2015, PMID 25904635), so CT carriers would be expected to have slightly higher FSH than TT carriers.

For women pursuing fertility workup, this genotype is unlikely to drive strong hormonal findings on its own. Its most relevant application is when interpreted alongside the rs6165/rs6166 coding-variant haplotype for a complete FSHR axis picture. In Colombian cohort data, rs2268361 participated in a synergistic three-locus model, suggesting its effect is amplified in certain FSHR genetic backgrounds.

CC “Risk Homozygote” High Risk Warning

Two C alleles — elevated PCOS susceptibility and higher basal FSH through this intronic FSHR locus

The C allele at rs2268361 tags an intronic regulatory haplotype associated with altered FSHR expression or activity in granulosa cells. CC homozygotes carry two doses of this effect, which translates to modestly elevated basal FSH — consistent with pituitary compensation for slightly reduced FSH receptor efficiency.

Cross-ethnic evidence from 2,718 European women (Saxena et al. 2015) confirms the T allele reduces FSH by approximately 0.15 standard deviations per allele, so CC carriers would be expected to have approximately 0.30 SD higher FSH than TT carriers. For a population where mean day-3 FSH is ~7 mIU/ml and SD is ~3 mIU/ml, this translates to approximately 0.9 mIU/ml higher FSH — detectable in aggregate but modest in an individual clinical context.

The Saudi Arabian study (PMID 31902981) found TT homozygosity associated with normal AMH in controls; by contrast, CC carriers are at the highest risk for the PCOS-associated AMH alterations at this locus, though the study was underpowered to quantify the CC vs TT AMH differential precisely.

The epistatic data (PMID 39273163) suggest that the CC genotype combined with other FSHR or nearby variants can produce synergistic effects on PCOS risk exceeding simple additive predictions. CC carriers who also carry the coding-variant risk haplotype (CC at rs6165, GG at rs6166) have three independent risk signals at the FSHR locus simultaneously.