rs10835638

mixedMag 4.5

This is a upstream gene variant variant in the FSHB gene.

Key Literature Trait Associations

Polycystic ovary syndrome

The T allele at rs10835638 has been associated with polycystic ovary syndrome (PCOS) in European women (OR=1.81, 95% CI 1.44–2.27, p=5×10⁻¹²) via GWAS Catalog study GCST010568. This effect likely reflects the FSHB locus on chromosome 11p14.1 previously implicated by Hayes et al. (2015) in a landmark PCOS GWAS (Nature Communications, n~4,978 total), which identified the nearby rs11031006 at genome-wide significance. The elevated LH/FSH ratio in T-allele carriers may drive the hypergonadotropic component of PCOS pathophysiology. The relatively small sample size of the directly associated study warrants cautious interpretation despite the highly significant p-value.

Dapas M et al. “Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis.” Plos Medicine 17(6):e1003132 (2020)

Allele T

OR 1.81

p 5.0e-12

N 4,455

Large GWAS

European

Hayes MG et al. “Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.” Nature Communications 6:7502 (2015)

Allele T

OR —

p —

N 4,978

Preliminary work

European

Serum FSH Levels

The T allele at the FSHB promoter position -211 reduces binding of the LHX3 homeodomain transcription factor, lowering FSHB gene transcription and circulating FSH levels. In a study of 1,054 Baltic men, each T allele reduced serum FSH by ~0.41 IU/L and was associated with reduced testicular volume, lower total testosterone, and lower inhibin-B. TT homozygous men may represent a pharmacogenetically distinct subgroup benefiting from FSH supplementation.

Tüttelmann F et al. “Combined effects of the variants FSHB -211G>T and FSHR 2039A>G on male reproductive parameters.” The Journal of Clinical Endocrinology and Metabolism (2012)

Allele T

OR —

β -0.510

p —

N 3,017

Preliminary work

European

Grigorova M et al. “Genetically determined dosage of follicle-stimulating hormone (FSH) affects male reproductive parameters.” The Journal of Clinical Endocrinology and Metabolism 96(9):E1534-E1541 (2011)

Allele T

OR —

β -0.410

p 1.1e-6

Preliminary work

“A GWAS in Idiopathic/Unexplained Infertile Men Detects a Genomic Region Determining Follicle-Stimulating Hormone Levels”

Allele T

OR —

p 5.5e-7

N 1,900

Small GWAS

European

“Effects of the FSH-β-subunit promoter polymorphism -211G->T on the hypothalamic-pituitary-ovarian axis in normally cycling women indicate a gender-specific regulation of gonadotropin secretion”

Allele T

OR —

β 2.050

p 3.0e-3

N 803

Preliminary work

European

“FSHB -211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women”

Allele T

OR —

β 0.800

p 1.2e-3

N 355

Candidate gene study

European

Male infertility

In men, the T allele lowers FSH secretion and is associated with impaired spermatogenesis. Tüttelmann et al. (2012) showed T-allele carriers have significantly smaller testes and lower sperm counts. Krenz et al. (2021) identified FSHB genotype as the strongest segregation marker among 2,742 idiopathic infertile men (p=2.2×10⁻¹⁶). Busch et al. (2019) found T-allele status significantly predicted TESE failure in 1,075 azoospermic men. Rull et al. (2018) found the T allele frequency doubled among idiopathic female infertility patients (23.6% vs. 12.4%), extending the reproductive impact to both sexes. The TT homozygote prevalence was 3× higher in infertile vs. fertile groups.

Krenz H et al. “FSHB Genotype Identified as a Relevant Diagnostic Parameter Revealed by Cluster Analysis of Men With Idiopathic Infertility.” Frontiers in Endocrinology (2021)

Allele T

OR —

p 2.2e-16

N 2,742

Large GWAS

European

Tüttelmann F et al. “Combined effects of the variants FSHB -211G>T and FSHR 2039A>G on male reproductive parameters.” The Journal of Clinical Endocrinology and Metabolism (2012)

Allele T

OR —

β -3.200

p —

N 3,017

Preliminary work

European

“FSHB -211 G>T Polymorphism as Predictor for TESE Success in Patients With Unexplained Azoospermia”

Allele T

OR —

p —

N 1,075

Preliminary work

European

Menstrual Cycle Length

The FSH-lowering T allele of rs10835638 is associated with longer menstrual cycles in women. A Mendelian randomisation study in up to 63,350 UK Biobank women found each T allele lengthened cycle by ~0.16 SD (approximately 1 day). This is consistent with lower FSH slowing follicular maturation and extending the follicular phase.

Ruth KS et al. “Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health.” Human Reproduction (oxford, England) 31(2):473-481 (2016)

Allele T

OR —

β 0.160

p 6.0e-16

Large GWAS

Endometriosis

Ruth et al. (2016) found the FSH-lowering T allele was associated with lower endometriosis risk (OR=0.79, p=4.1×10⁻⁴) in a large population-based study (up to 63,350 women). A candidate-gene study by Bianco et al. (2023) in 326 Brazilian women with endometriosis and 482 controls found overall genotype frequencies did not differ significantly, but the T allele was more common in minimal/mild endometriosis cases under a recessive genetic model. The paradox of lower risk at the population level but enrichment in mild disease may reflect the FSH-lowering effect reducing proliferative endometrial stimulation, with stage-specific interactions.

Allele T

OR 0.79

p 4.1e-4

N 63,350

Preliminary work

European

Bianco B et al. “Implication of FSHB rs10835638 variant in endometriosis in Brazilian women.” Einstein (sao Paulo, Brazil) (2023)

Allele T

OR —

p —

N 808

Preliminary work

multi-ancestry

Age at thelarche

Busch et al. (2018) studied 1,478 girls followed prospectively through puberty and found the T allele was associated with earlier thelarche (breast development onset) by approximately 0.19 years (95% CI 0.06–0.31, p=0.004), adjusted for BMI z-score. No significant association was found with age at menarche (p=0.97). This suggests that FSH — the physiological effector of this SNP — plays a specific role in early pubertal breast development but not in the timing of first menstruation, pointing to differential regulation of the two pubertal milestones.

“Differential Impact of Genetic Loci on Age at Thelarche and Menarche in Healthy Girls”

Allele T

OR —

β -0.190 ±0.060

p 4.0e-3

N 1,478

Preliminary work

European

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GWAS Catalog Trait Associations (1)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

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ClinVar annotation

Association

1 submitter2 publications

Hypogonadotropic hypogonadism 24 without anosmia (HH24)

View on ClinVar →

Gene information from NCBI Gene. Variant classifications from ClinVar.

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