rs2268363 — FSHR FSHR ART Response Variant

Intronic variant in the FSH receptor gene; identified in a genome-wide association study as associated with post-radiotherapy erectile dysfunction risk in African-American men; located in close proximity to rs2268361 and serves as an FSHR haplotype tag with potential relevance to gonadotropin signaling

See your personal result for FSHR

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.

FSHR rs2268363 — An FSHR Intronic Tag Variant at the ART-Relevant FSHR Locus

The follicle-stimulating hormone receptor (FSHR) is one of the most important genes in reproductive medicine. Encoded on chromosome 2q16.2 with the gene running on the minus strand, FSHR mediates the action of follicle-stimulating hormone (FSH) in both females — where it drives granulosa cell maturation, folliculogenesis, and ovarian response to exogenous gonadotropin stimulation — and in males, where it supports Sertoli cell function and spermatogenesis. Coding variants in FSHR, particularly rs6165 (Ala307Thr)11 rs6165 (Ala307Thr)
Located in the extracellular hinge region; removes an O-linked glycosylation site and rs6166 (Asn680Ser)22 rs6166 (Asn680Ser)
Located in the intracellular domain; alters cAMP signaling kinetics after FSH binding, are among the most studied pharmacogenomic variants in IVF medicine.

rs2268363 lies in an intron of FSHR at GRCh38 position chr2:48,974,189, approximately 284 base pairs from the closely related intronic variant rs2268361. Its position within the gene means it does not directly alter the FSH receptor protein. Instead, as an intronic tag variant, it may capture information about the underlying haplotype architecture of the FSHR locus — the combination of nearby variants that a given chromosome carries. The G allele occurs at 16% globally, with pronounced ancestry variation: approximately 14% in Europeans, 25% in East Asians, and 42% in African populations.

The Mechanism

As an intronic variant with a CADD score of approximately 11, rs2268363 has no predicted direct functional consequence on the FSH receptor protein. Its biological significance, to the extent it exists, derives from linkage disequilibrium with nearby functional variants across the FSHR locus. The FSHR gene harbors multiple well-characterized regulatory and coding variants — including the promoter SNP rs1394205 (G-29A), which reduces FSHR transcription, and the coding pair rs6165/rs6166 that form the Ala307Thr-Asn680Ser haplotype associated with reduced FSH receptor sensitivity. An intronic variant in close proximity to rs2268361 may partially tag one or more of these haplotypes, particularly in populations where relevant LD patterns are maintained.

The Evidence

The only published genome-wide significant association for rs2268363 is its identification in a 2010 GWAS by Kerns et al.33 a 2010 GWAS by Kerns et al.
Genome-wide association study to identify SNPs associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys, 2010 as associated with [erectile dysfunction | Inability to achieve or maintain an erection, here specifically as a late adverse effect of pelvic radiation therapy] after radiotherapy for prostate cancer in African-American men (79 patients total; unadjusted p=5.46×10⁻⁸, Bonferroni p=0.028). The investigators proposed that FSHR expression in penile vascular and neural structures might modify radiation sensitivity in these tissues.

This finding was not validated in a subsequent attempt: Schack et al. 201744 Schack et al. 2017
Validation of genetic predictors of late radiation-induced morbidity in prostate cancer patients. Acta Oncol, 2017 tested rs2268363 among nine radiotherapy-morbidity SNPs in a Danish prostate cancer cohort and could not replicate the original GWAS signal. This is not unusual for GWAS findings from small discovery cohorts — the Kerns 2010 study included only 79 African-American patients, and genomic signals from underpowered studies frequently fail replication.

No direct evidence links rs2268363 specifically to IVF outcomes or ovarian stimulation response. The fertility pharmacogenomics literature on FSHR focuses primarily on rs6165, rs6166, rs1394205, and rs2268361 — all of which are distinct variants. Attributing ART relevance to rs2268363 would require either direct evidence (which is absent) or demonstration of strong linkage disequilibrium with a variant that does have such evidence, which has not been published.

The nearby rs2268361 (284 bp upstream) has been studied in PCOS susceptibility cohorts55 cohorts
Saxena et al. 2015, Human Reproduction: rs2268361-T associated with lower FSH levels in European women, P=0.0029 and reproductive phenotypes, but it is a distinct variant and its LD relationship with rs2268363 has not been reported in the published literature.

Practical Implications

For males: the G allele at rs2268363 was associated with a higher risk of erectile dysfunction following pelvic radiotherapy for prostate cancer in one African-American cohort — an association that was not subsequently validated. Men of African ancestry undergoing pelvic radiation therapy may wish to note this result in discussions with radiation oncologists about post-treatment sexual health monitoring, though the evidence does not yet support clinical use of this genotype for decision-making.

For females: there is no published evidence that rs2268363 specifically affects ovarian stimulation response, IVF outcomes, or FSH receptor function in the context of ART. Women who are concerned about their FSH receptor pharmacogenomics profile should prioritize results from rs6165, rs6166, and rs1394205 — the coding and promoter variants with substantial clinical evidence.

The FSHR locus is important for reproductive pharmacogenomics, and rs2268363 is a marker within that locus. As sequencing studies become larger and more ethnically diverse — particularly including African ancestry populations where the G allele is most common — the haplotype contribution of rs2268363 to FSH receptor function may be clarified.

Interactions

rs2268361 (FSHR intronic): The nearest characterized neighbor in FSHR, 284 bp downstream. rs2268361-T is associated with lower basal FSH levels in European women and has been studied in PCOS cohorts across multiple ancestries. The LD relationship between rs2268361 and rs2268363 in different populations has not been characterized in published studies but is likely relevant given their physical proximity.

rs6165 and rs6166 (FSHR coding variants): The primary pharmacogenomic variants at this locus with well-documented effects on ovarian stimulation response in IVF. These coding variants, which form the Ala307Thr-Asn680Ser haplotype, are the actionable variants for ART planning. Their LD relationship with rs2268363 across the full FSHR haplotype block has not been directly reported but is a relevant question for future multi-variant FSHR studies.

rs1394205 (FSHR promoter G-29A): The promoter variant that reduces FSHR transcription; independently studied in additive diplotype analyses alongside rs6165/rs6166. Like rs2268363, it is non-coding, but its mechanistic role (regulating receptor expression level) is established in functional studies.

Genotype Interpretations

What each possible genotype means for this variant.

AA Common Allele Normal

Two copies of the reference A allele — no documented ART or fertility risk from this variant

You carry two copies of the A allele at rs2268363, the common variant in most populations (approximately 71% of people globally share this genotype). This represents the GRCh38 plus-strand reference allele and is the predominant genotype across European (~75% AA), South Asian (~72% AA), and Latin American populations. It is less common in African populations, where the G allele reaches 42% frequency.

There is no published evidence that the AA genotype at rs2268363 affects FSH receptor function, ovarian stimulation response, IVF outcomes, or any other fertility-related phenotype. The one genome-wide association study that examined this variant was in the context of prostate cancer radiotherapy, not fertility, and the original finding was not replicated in a subsequent validation study.

AG Mixed Allele Intermediate

One A and one G allele — heterozygous for this FSHR intronic variant; no established fertility effect

rs2268363 sits within an intron of FSHR, approximately 284 base pairs from the intronic variant rs2268361 (which itself has been studied in PCOS and FSH-level associations). Heterozygosity at this position places one chromosome with the A-allele haplotype and one with the G-allele haplotype at this FSHR intron. Whether these haplotype backgrounds differ in their co-inheritance with nearby functional variants — such as the Ala307Thr/Asn680Ser pair (rs6165/rs6166) or the promoter G-29A variant (rs1394205) — has not been directly characterized in the published literature.

The CADD score of ~11 suggests limited functional impact at this nucleotide position, consistent with an intronic location and without strong conservation signals (GERP -2.62). For men undergoing pelvic radiotherapy, the G allele at rs2268363 was identified as a potential modulator of post-treatment erectile function, but the clinical utility remains unestablished due to the failure of the original finding to replicate.

GG Minor Allele Decreased

Two copies of the G allele — the minor variant globally, most common in African populations; associated with post-radiotherapy erectile dysfunction in one unvalidated GWAS

The GG homozygous genotype at rs2268363 places you in the minor haplotype background at this FSHR intronic position. Because the variant is intronic with low conservation (GERP -2.62), GG homozygosity is unlikely to directly affect FSH receptor protein function. If the G allele does modulate any aspect of FSHR biology, it likely does so through its co-inheritance with nearby haplotype variants across the FSHR locus — a relationship that has not been directly characterized in published studies.

For men of African ancestry (where GG occurs at ~18%), the 2010 GWAS finding is the most directly relevant evidence: G-allele homozygotes (and heterozygotes) in a predominantly African-American prostate cancer cohort showed a signal for post-radiotherapy erectile dysfunction susceptibility. The mechanism proposed was that FSHR expression in penile vasculature might modify radiation-induced vascular injury. The GG genotype would represent the maximum exposure to this putative effect, though the finding's failure to validate in a European cohort limits clinical application.

For fertility contexts — whether ovarian stimulation response in women or spermatogenic effects in men — the evidence base for rs2268363 specifically is absent. The GG genotype at this locus should not be interpreted as indicating high ART risk independent of the established FSHR coding and promoter variants.