rs4806660 — TMEM150B

TMEM150B 19q13.42 — The Autophagy Modulator and Your Ovarian Clock

On chromosome 19 at band q13.42, within a dense cluster of reproductive-aging loci, lies a variant that has drawn attention for its unexpectedly large effect on early menopause risk. The rs4806660 SNP falls within the gene TMEM150B — also known as DRAM3 (Damage-Regulated Autophagy Modulator 3) — a transmembrane protein expressed in oocytes whose precise role in reproductive aging is still being worked out.

A note on gene attribution: early GWAS publications initially assigned this locus to the nearby BRSK1 gene (also at 19q13.42) based on physical proximity. Subsequent fine-mapping established that rs4806660 and the lead SNP rs1172822 are in near-complete linkage disequilibrium (R²=0.965) and both fall within the TMEM150B gene body. Some older references still label this locus as BRSK1 or "ZNF346" (a chromosome 5 gene unrelated to this locus); the current consensus assigns it to TMEM150B.

The Mechanism

TMEM150B encodes a five-transmembrane-domain protein that belongs to the DRAM family¹¹ DRAM family
Damage-Regulated Autophagy Modulators — a class of lysosomal and endosomal membrane proteins that regulate autophagic flux under conditions of cellular stress. The protein localises to lysosomes, endosomes, and the plasma membrane. Overexpression studies show that TMEM150B promotes autophagosome accumulation and enhances autophagic flux under baseline conditions; it also promotes cell survival during glucose deprivation through an autophagy-independent mechanism.

Autophagy²² Autophagy
the cellular self-digestion pathway that recycles damaged organelles and proteins to maintain oocyte quality is increasingly recognised as a critical maintenance system in the dormant oocyte pool. Human oocytes are arrested for decades; their long-term viability depends on continuous quality-control mechanisms to handle accumulated protein aggregates and dysfunctional mitochondria. Defective autophagy in granulosa cells and oocytes has been linked to accelerated follicular atresia and POI in animal models.

rs4806660 is an intronic variant, meaning it does not alter the protein sequence. The most likely mechanism is cis-regulatory³³ cis-regulatory
affecting the expression level of a nearby gene rather than its protein sequence: the C allele may alter TMEM150B expression in ovarian cells in ways that subtly compromise the autophagy-mediated quality control sustaining the follicle pool. However, the precise regulatory effect of this specific intronic change on TMEM150B expression in human ovarian tissue has not yet been directly characterised.

It is important to note that when Tmem150b was completely knocked out in mice, female fertility was normal and hormone levels were unchanged⁴⁴ female fertility was normal and hormone levels were unchanged
Liu et al. 2020, Scientific Reports. This may indicate functional redundancy within the DRAM family, species differences in the specific gene's requirement, or that the effect of the common human intronic variant operates through a mechanism distinct from complete gene ablation.

The Evidence

The 19q13.42 locus was first identified by Stolk et al. 2009⁵⁵ Stolk et al. 2009
Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nature Genetics, 2009 in a two-stage GWAS of 2,979 European women (Rotterdam Study and TwinsUK), with the lead SNP rs1172822 reaching p = 6.3 × 10⁻¹¹. Subsequent fine-mapping using imputed data identified rs4806660 as an additional SNP in the same LD block with even stronger statistical support.

The most informative study for clinical interpretation is the Breakthrough Generations Study⁶⁶ Breakthrough Generations Study
Murray et al. 2011, Human Molecular Genetics, ~2,000 women with early menopause before age 46 versus controls. In this case-control design, each C allele was associated with an odds ratio of 1.45 (95% CI 1.32–1.59, p = 8.88 × 10⁻¹⁶) for experiencing menopause before age 46. Notably, the observed odds ratio was substantially larger than the 1.20 expected from quantitative trait estimates — suggesting a non-linear effect where the C allele may have a disproportionate impact on the earliest end of the menopause-age distribution, affecting those most biologically susceptible to early follicular depletion.

Beyond menopause timing, a Brazilian IVF cohort study by Setti et al. 2012⁷⁷ Setti et al. 2012
A chromosome 19 locus positively influences the number of retrieved oocytes during stimulated cycles in Brazilian women. Journal of Assisted Reproduction and Genetics, 2012 found that women carrying the T allele (the protective/common allele) had significantly more antral follicles (+2.54 per cycle, P=0.041) and more retrieved oocytes (+1.41 per cycle, P=0.041) during controlled ovarian stimulation — providing a direct, clinically measurable link between this variant and the functional ovarian reserve available for IVF.

A Mashhad cohort study 2021⁸⁸ Mashhad cohort study 2021
Genetic Determinants of Premature Menopause in a Mashhad Population Cohort. IJFS, 2021 found that the C allele in Iranian women was associated with premature menopause risk (OR 3.09, 95% CI 1.17–8.16 in a recessive model), though this did not survive Bonferroni correction. The direction of effect is consistent with European data, suggesting the association may generalise across Middle Eastern populations, but effect sizes remain uncertain outside the original European GWAS context.

Population differences are striking: the C allele is common in Europeans (~36%), African-ancestry (~37%), and South Asian (~41%) populations, but is found at substantially lower frequency in East Asian populations (~8%). This means the variant's contribution to population-level menopause timing variation is much smaller in East Asian women.

Practical Actions

For women with the common TT genotype, this variant suggests a somewhat lower genetic load for early follicular depletion at this locus. AMH testing remains the most direct measure of current reserve and is appropriate for fertility planning regardless of genotype.

For C allele carriers, the primary implication is a modestly elevated probability of earlier reproductive aging — a probabilistic shift, not a certainty. The variant may be particularly relevant when ovarian response to gonadotropin stimulation is lower than expected, since Setti et al. suggest this locus influences the gonadotropin-responsive follicle pool.

Interactions

TMEM150B rs4806660 + MCM8 rs16991615 (19q13.42 + 20p12.3 menopause loci): MCM8 rs16991615 (E341K, DNA repair helicase) is among the most robustly replicated menopause-timing loci with an effect of approximately 1 year per A allele. Women carrying the common risk GG genotype at MCM8 (absent protective allele) who also carry one or two C alleles at rs4806660 accumulate two independent additive hits on follicular reserve through distinct biological pathways — DNA repair and autophagy regulation. A compound action for this combination emphasising early AMH baseline testing and proactive reproductive timeline discussion is warranted.

TMEM150B rs4806660 + PRRC2A rs1046089 (immune-linked menopause locus): rs1046089 in the HLA-region PRRC2A gene acts through immune modulation of follicular atresia. Combined C allele burden at rs4806660 alongside the A allele at rs1046089 converges on reproductive aging through two further independent mechanisms (autophagy dysregulation and immune-mediated follicle depletion). Women with risk alleles at both loci may benefit from earlier fertility assessment than either variant alone would indicate.