rs116098458 — KIF2B

Rare intronic variant in a lncRNA antisense to KIF2B (chromosome 17q22), identified in the Ruth et al. 2021 Nature GWAS as associated with age at natural menopause; KIF2B encodes a kinesin-13 microtubule depolymerase essential for bipolar spindle assembly during oocyte meiosis

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KIF2B rs116098458 — Spindle Assembly, Oocyte Quality, and Menopause Timing

The fidelity of chromosome segregation during female meiosis depends critically on the construction and function of the meiotic spindle — the microtubule apparatus that physically moves chromosomes to opposite poles of the oocyte. KIF2B (Kinesin Family Member 2B) is a member of the kinesin-13 family of microtubule depolymerases11 KIF2B (Kinesin Family Member 2B) is a member of the kinesin-13 family of microtubule depolymerases
KIF2B, also known as KIF2B/Kif2b, belongs to the kinesin-13 subfamily along with KIF2A and KIF2C (MCAK). Unlike motile kinesins, kinesin-13 members do not walk along microtubules — they bind microtubule ends and induce depolymerization to regulate spindle dynamics. rs116098458 is an intronic variant in a long non-coding RNA (lncRNA) located antisense to KIF2B at chromosome 17q22, identified in the 2021 Ruth et al. Nature genome-wide association study as associated with variation in age at natural menopause.

The Mechanism

KIF2B is expressed at low levels in dividing cells but plays a distinct, non-redundant role in the early stages of spindle bipolarity. Depletion of KIF2B in human cells causes over 70% of mitoses to produce monopolar or disorganized spindles, with chromosome movement velocity reduced to approximately 20% of normal22 Depletion of KIF2B in human cells causes over 70% of mitoses to produce monopolar or disorganized spindles, with chromosome movement velocity reduced to approximately 20% of normal
Manning et al. 2007 Mol Biol Cell — the three kinesin-13 paralogs have distinct, non-overlapping functions during mitosis. In oocytes, this matters acutely: meiotic spindle assembly occurs without centrosomes — an acentrosomal process that is particularly dependent on coordinated microtubule depolymerase activity to achieve bipolar organization from a disordered starting state. Failure of spindle bipolarity leads to chromosome segregation errors and oocyte aneuploidy33 chromosome segregation errors and oocyte aneuploidy
Aneuploidy — the wrong number of chromosomes in an egg — is the most common cause of embryo arrest, miscarriage, and implantation failure in IVF; it increases steeply with maternal age as spindle machinery becomes less efficient.

The rs116098458 variant lies within a lncRNA transcribed antisense to KIF2B. Antisense lncRNAs can regulate their sense-strand gene partners through several mechanisms — transcriptional interference, chromatin remodeling, RNA–RNA base-pairing, or by acting as competing endogenous RNAs. Whether this specific variant alters KIF2B expression in oocytes or granulosa cells has not yet been characterized mechanistically. Its detection in a large-scale GWAS of menopause timing places it at a biologically plausible locus: the chromosome 17q22 region encompasses KIF2B and its antisense regulatory non-coding transcripts, and spindle assembly fidelity is a documented contributor to oocyte quality across the reproductive lifespan.

The Evidence

The primary evidence for rs116098458 comes from the Ruth, Day et al. 2021 Nature GWAS44 Ruth, Day et al. 2021 Nature GWAS
Genetic insights into biological mechanisms governing human ovarian ageing. Nature 596:393–397, 2021, which analysed age at natural menopause in approximately 200,000 women of European ancestry and identified 290 genome-wide significant loci. The study implicates DNA damage response, meiotic recombination, and spindle assembly genes as the biological drivers of ovarian reserve depletion — the process that ultimately determines when menopause occurs. Loci at spindle assembly genes fit a coherent mechanistic model: accumulating errors in meiotic chromosome segregation over thousands of ovarian cycles deplete the functional follicle pool.

It is important to note that the T allele at rs116098458 is extremely rare: approximately 0.5% globally in gnomAD, essentially absent in individuals of European and East Asian ancestry, and present at approximately 1.3% in individuals of African ancestry. This frequency distribution means the GWAS association was likely driven by African-ancestry participants or discovered in trans-ethnic analyses. Effect size estimates from the primary publication are not publicly resolved for this specific variant at the time of writing.

The biological context of KIF2B in spindle assembly is mechanistically solid. The kinesin-13 proteins KIF2A, KIF2B, and KIF2C have distinct non-redundant roles in bipolar spindle establishment and chromosome movement55 kinesin-13 proteins KIF2A, KIF2B, and KIF2C have distinct non-redundant roles in bipolar spindle establishment and chromosome movement
Manning et al. 2007 Mol Biol Cell — each kinesin-13 paralog localizes to different spindle components and acts at different cell-cycle stages. KIF2B acts specifically in early spindle assembly, and its absence cannot be compensated by KIF2A or MCAK.

Practical Implications

Because this variant is extremely rare and absent in most ancestry groups, its direct relevance is narrow. Individuals of African ancestry who carry the T allele have a slightly altered KIF2B-locus regulatory configuration whose net effect on oocyte spindle assembly and menopause timing is not yet precisely quantified. The general principle — that efficient meiotic spindle assembly is protective for long-term ovarian function — applies regardless of genotype and is supported by strong mechanistic data. Exposures that impair spindle microtubule dynamics (persistent organic pollutants with microtubule-binding properties, heavy metals such as cadmium, bisphenol A) are plausible environmental modifiers.

Interactions

rs10804920 (TP63 intronic variant): TP63 encodes the master DNA-damage checkpoint transcription factor in primordial follicle oocytes. While TP63 and KIF2B operate through mechanistically distinct pathways (DNA damage response vs. spindle assembly), both ultimately affect the rate of follicle pool depletion. Spindle defects during meiosis can generate DNA damage as a secondary consequence of chromosome missegregation, potentially activating the TAp63 checkpoint downstream. Women carrying risk alleles at both a spindle assembly locus and a DNA-damage checkpoint locus may have compounded vulnerability, though no published study has examined this interaction directly.

rs2307449 (BRSK1) and rs244715 (ZNF346/UIMC1): Other menopause-timing loci in the database that operate through DNA double-strand break repair (BRSK1) and BRCA1 complex function (UIMC1). Combined polygenic burden from spindle assembly and DNA repair loci could warrant proactive ovarian reserve assessment.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

Common genotype — baseline KIF2B locus configuration; standard menopause timing trajectory

The T allele at rs116098458 is extremely rare — essentially absent in European and East Asian populations and present at approximately 1.3% in African-ancestry individuals. The population-wide frequency means that for the vast majority of people reading this result, the CC genotype is simply the expected finding. There is no known risk or benefit conferred by this genotype; it represents the ancestrally common configuration at this locus.

Age at natural menopause is determined by hundreds of genetic variants, lifestyle factors, and cumulative environmental exposures. The absence of the rare T allele at this locus is not informative about your overall menopause timing trajectory — other variants in the GeneOps database provide stronger and more globally applicable signals for ovarian aging.

CT Intermediate

One rare T allele — variant at the KIF2B-antisense lncRNA locus associated with altered menopause timing

KIF2B is required for bipolar spindle assembly: when KIF2B is depleted in human cells, over 70% of cell divisions produce monopolar or disorganized spindles and chromosome movement velocity falls to approximately 20% of normal (Manning et al. 2007, Mol Biol Cell). In oocytes, which undergo acentrosomal spindle assembly without the centrosomes that guide somatic cell division, correct microtubule depolymerase activity is especially critical for achieving the bipolar spindle geometry needed for accurate chromosome segregation. Spindle defects in oocytes lead to aneuploidy — the wrong chromosome number in the resulting egg — which is the leading cause of failed implantation, miscarriage, and IVF failure.

The rs116098458 T allele sits within an antisense lncRNA that may regulate KIF2B expression or function in oocytes or granulosa cells, but the specific molecular mechanism has not yet been characterized. The GWAS association with menopause timing is plausible given KIF2B's spindle role, but effect size data for this individual variant are not resolved in the published literature.

Given the extreme rarity of the T allele (predominantly seen in African-ancestry individuals), this result is most informative in that population context.

TT High Risk

Two rare T alleles — homozygous for the KIF2B-locus rare allele; extremely uncommon globally

The extreme rarity of TT homozygosity (expected frequency ~0.0003% globally) means that essentially no population-scale data exists on the phenotypic consequences of this genotype specifically. Effect estimates from GWAS are typically derived from the CT heterozygote class, and the homozygous TT effect is extrapolated by assuming additivity.

KIF2B's role in spindle bipolarity is well-established in cellular models: its absence produces monopolar or chaotic spindles with severely reduced chromosome segregation velocity. In oocytes, which lack centrosomes and rely entirely on microtubule-based self-organization to achieve spindle bipolarity, any perturbation to the KIF2B-mediated microtubule depolymerization step has the potential to increase chromosomal aneuploidy rates and impair oocyte quality over time.

If this result is confirmed by a clinical-grade sequencing report, referral to a reproductive endocrinologist or genetic counselor for interpretation in the context of your full clinical picture is appropriate. The rarity of this genotype means personalized clinical assessment will be more informative than population-derived statistics alone.