rs10183486 — TLK1

Intronic variant in TLK1 (tousled like kinase 1), a DNA-damage-repair and chromatin-assembly kinase; each copy of the T allele may be associated with earlier age at natural menopause by approximately 10 weeks, suggesting a modest influence on ovarian reserve and reproductive lifespan

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TLK1 rs10183486 — A DNA-Repair Kinase Variant That May Hasten Ovarian Aging

The timing of menopause is one of the strongest proxies for the size and health of the ovarian reserve — the pool of follicles a woman is born with and slowly depletes across her reproductive life. Women who reach menopause earlier tend to have lower anti-Müllerian hormone (AMH)11 anti-Müllerian hormone (AMH)
the granulosa-cell glycoprotein that serves as the best single blood marker of how many follicles remain at every age, and a greater susceptibility to premature ovarian insufficiency (POI). Genome-wide association studies have repeatedly confirmed that DNA-damage-response genes cluster at the top of the list of genetic determinants of reproductive lifespan — and TLK1 is one of the clearest examples.

The Mechanism

TLK1 encodes a nuclear serine/threonine kinase whose activity is tightly coupled to active DNA replication, reaching peak levels during S phase. Its two best-characterised substrates are Asf122 Asf1
anti-silencing function 1, a histone H3/H4 chaperone that is essential for nucleosome assembly onto newly synthesised and repaired DNA and RAD9, a scaffold protein in the DNA damage checkpoint. By phosphorylating Asf1, TLK1 ensures that chromatin is re-packaged efficiently behind the replication fork and at sites of double-strand break repair; by modulating RAD9, it controls how long the checkpoint remains active after damage is resolved.

The ovaries are extraordinarily dependent on accurate DNA repair. Primary oocytes are arrested in meiotic prophase I for decades — throughout which time they must faithfully maintain their genetic integrity against oxidative damage, metabolic stress, and the natural accumulation of replication errors from earlier development. Defects in homologous-recombination and chromatin-assembly genes are a well-established cause of accelerated follicle depletion33 Defects in homologous-recombination and chromatin-assembly genes are a well-established cause of accelerated follicle depletion
See Ruth et al. 2021 (Nature) for a comprehensive map of DNA-repair loci governing ovarian ageing. The rs10183486 T allele at the TLK1 locus is intronic and does not change the TLK1 protein directly; its effect is likely mediated through altered splicing efficiency or regulatory element function that reduces TLK1 expression or activity in ovarian tissue.

The Evidence

The strongest evidence comes from a meta-analysis of 22 genome-wide association studies by Stolk et al. 201244 meta-analysis of 22 genome-wide association studies by Stolk et al. 2012
Meta-analyses identify 13 loci associated with age at menopause. Nature Genetics, 44:260–268, which examined 38,968 women of European descent and replicated findings in a further 14,435 women. The TLK1 locus reached genome-wide significance at P = 2.21×10⁻¹⁴, with each T allele associated with approximately 10 fewer weeks (beta = -0.196 years) before menopause onset. Among the 13 novel loci identified in that study, TLK1 was one of eight genes implicated in DNA-damage response and repair pathways — a striking enrichment that has been replicated in larger subsequent studies.

A cross-sectional cohort study of Iranian women by Mirinezhad et al. 202155 cross-sectional cohort study of Iranian women by Mirinezhad et al. 2021
Genetic Determinants of Premature Menopause in a Mashhad Population Cohort. Int J Fertil Steril, 2021 examined rs10183486 directly in 117 women with premature menopause and 183 controls. The T allele was more frequent in cases (36%) than controls (27%), with the TT homozygous genotype associated with an approximately 3.3-fold higher odds of premature menopause compared with CC homozygotes (OR 3.29, 95% CI 1.34–8.09, P = 0.010). A subsequent analysis from the same cohort found that rs10183486 genotype was also associated with altered hs-CRP levels, hinting at an inflammatory component in the TLK1–ovarian axis. Note that associations in the Mashhad cohort did not survive Bonferroni correction for multiple comparisons, reflecting the modest sample size; the primary evidence base remains the large European GWAS.

Population specificity is noteworthy: a replication study in Chinese women66 replication study in Chinese women
Evaluating GWAS-Identified SNPs for Age at Natural Menopause among Chinese Women. PLoS ONE 2013 found that rs10183486 did not associate with menopause age in East Asian women (P = 0.325). This may reflect that rs10183486 is a tag SNP in high linkage disequilibrium with the true causal variant in Europeans (r² = 0.86 with rs4667673 in European panels) but not in East Asian populations (r² = 0.005), rather than a true null association.

Practical Actions

The clinical implication is modest but meaningful for reproductive planning. Each T allele may be associated with approximately 10 fewer weeks of reproductive lifespan; the TT genotype may be associated with up to 20 fewer weeks earlier menopause onset relative to CC individuals. For women planning families, this may translate into a somewhat earlier timeline for ovarian reserve monitoring.

Because the variant acts through a DNA-repair pathway, antioxidant support that protects oocytes from oxidative DNA damage is a plausible intervention — though direct evidence for supplementation reversing TLK1-pathway effects is not yet established. Reproductive endocrinologists increasingly use baseline AMH measurement in women with a family history of early menopause or who carry genetic risk variants at loci like TLK1 to guide family-planning timelines.

Interactions

The strongest documented interaction relevant to ovarian reserve is with rs16991615 (MCM8), another DNA-repair gene locus associated with early menopause and AMH levels in multiple cohorts. Both TLK1 and MCM8 operate in pathways required for accurate DNA replication and repair; women carrying T alleles at both loci may have additive reduction in reproductive lifespan, though a formal compound analysis of this pair has not been published. In the Stolk 2012 meta-analysis, the ovarian aging signal from DNA-repair loci (including TLK1, MCM8, HELQ, EXO1, FANCI, POLG, PRIM1) was collectively enriched beyond what individual loci would predict, suggesting these variants act partially through convergent pathways. See rs16991615 for the MCM8 profile.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

Typical TLK1 function — no increased ovarian aging signal at this locus

The CC genotype represents the reference state at this locus. In the landmark Stolk et al. 2012 GWAS (38,968 European women), CC homozygotes served as the baseline group, with no downward shift in age at natural menopause attributed to the TLK1 locus. TLK1 expression and its downstream chromatin-assembly and DNA-repair functions are expected to be unperturbed by this variant in CC individuals.

This does not mean ovarian reserve is guaranteed to be normal — AMH and antral follicle counts are influenced by dozens of genetic loci as well as environmental exposures, lifestyle, and medical history. The CC genotype at rs10183486 simply removes one known genetic contributor to earlier reserve decline from consideration.

CT One T allele — mild ovarian aging signal Intermediate

One copy of the T allele — may be associated with modestly earlier menopause

The T allele at the TLK1 locus acts in an additive manner — CT heterozygotes fall between CC and TT individuals in terms of menopause timing. The ~10-week earlier onset per allele is a population-average estimate from a large European GWAS. At the individual level, this means CT individuals may have slightly lower AMH on average for their age than CC individuals, all else equal, but the overlap between groups is substantial and individual AMH measurements are needed to assess reserve directly.

The Iranian Mashhad cohort study (Mirinezhad et al. 2021, 300 participants) found CT genotype was more common in premature menopause cases than controls (40.4% vs 59.6%), though the dominant-model OR of 1.53 (95% CI 0.96–2.46) was not statistically significant at the P < 0.006 Bonferroni threshold, limiting the confidence in ascribing a specific risk magnitude to heterozygotes in that smaller study.

TT Two T alleles — stronger ovarian aging signal High Risk

Two T alleles — may be associated with earlier menopause and reduced ovarian reserve

TT homozygosity at rs10183486 places you at the highest-risk end of the TLK1 locus distribution for reproductive aging. The variant is intronic and does not alter TLK1 protein directly, but it likely reduces TLK1 activity in the ovary through regulatory or splicing effects. TLK1 normally phosphorylates the Asf1a/b histone chaperone during DNA replication and repair; reduced TLK1 activity may impair the efficiency with which oocytes and granulosa cells package and repair DNA, potentially accelerating the accumulation of damage that drives follicle apoptosis.

Important caveats: (1) The GWAS was conducted in European-ancestry women; the TT genotype is uncommon in East Asian populations (T allele frequency ~7%) so the risk estimate does not translate to all ancestries. (2) The effect size (~20 fewer weeks for TT vs CC) is a population average — your actual age at menopause is determined by dozens of genetic and environmental factors. (3) No ClinVar entry or clinical guideline exists for this variant. An AMH measurement is the most direct way to assess your current reserve.