Expressive

rs10789181 (DNAJC6): Age at Menarche Variant

Key takeaways

  • rs10789181 is one of 123 genetic signals linked to age at first menstrual period in a study of over 182,000 women
  • Together, these 123 variants explain about 2.7% of variation in menarche timing, reflecting a highly polygenic trait where many genes each contribute a small amount
  • The alternate allele reduces activity of LEPROT, a leptin receptor-related gene, across at least eight brain regions including the hypothalamus
  • Many menarche-associated loci, including this one, show consistent effects on pubertal timing in both boys and girls

Key takeaways

  • rs10789181 lies in the DNAJC6 gene region and is one of 123 independent genetic signals for age at first menstrual period (menarche) identified across over 182,000 women
  • The 123-variant set containing this signal explains about 2.7% of the variation in menarche timing in independent replication, reflecting a highly polygenic trait where many genes each contribute a small share
  • The alternate allele is linked to reduced activity of LEPROT (leptin receptor overlapping transcript) across at least eight brain regions, including the hypothalamus, caudate, and amygdala
  • Many menarche-associated loci show consistent effects on broader pubertal timing in both girls and boys

What the research says

A genome-wide meta-analysis combining data from 57 studies and up to 182,416 women of European descent identified 123 independent signals at 106 genomic loci reaching genome-wide significance (P < 5 x 10^-8) for association with age at menarche, and rs10789181 in DNAJC6 is among these signals. In an independent replication sample of 8,689 women, these 123 variants together explained 2.71% of variance in menarche age; incorporating all autosomal variants raised this estimate to 15.8% (standard error 3.6%), indicating that hundreds of common variants collectively drive the trait. Pathway analyses implicated nuclear hormone receptor signaling, including retinoic acid pathways and gamma-aminobutyric acid type B2 (GABA-B2) receptor signaling, as candidate mechanisms regulating pubertal timing.

Reported associations

  • Age at menarche: This variant is one of 123 genome-wide significant signals (P < 5 x 10^-8) found across 106 loci in a meta-analysis of up to 182,416 women of European descent from 57 studies; the full 123-variant set explains 2.71% of variance in an independent replication cohort (n=8,689)
  • General pubertal timing (both sexes): 90 of 106 menarche-associated loci showed consistent directional effects on Tanner stage (a clinical scale of physical pubertal development) in boys and girls combined (binomial sign test P = 1.1 x 10^-13), and 72 of 106 were consistent in boys alone, suggesting the underlying biology operates across sexes
  • LEPROT brain expression (eQTL): The alternate allele at this locus is linked to reduced LEPROT (leptin receptor overlapping transcript) expression in eight brain regions, including the hypothalamus, caudate basal ganglia, amygdala, putamen, nucleus accumbens, anterior cingulate cortex, frontal cortex, and cortex broadly GTEx Portal

Evidence quality

The menarche GWAS underpinning this entry is among the largest for a reproductive trait, pooling array-wide data from 132,989 women plus targeted genotyping data from an additional 49,427 women across 57 studies of European-descent participants. The genome-wide significance threshold (P < 5 x 10^-8) was applied, and directional replication was confirmed: 104 of 123 signals showed concordant associations in an independent sample of 8,689 women (binomial P = 2.2 x 10^-15), with 35 reaching nominal significance (P < 0.05) in that sample. The provided study excerpts do not report a variant-specific effect size or beta coefficient for rs10789181 in isolation, so individual effect magnitude for this signal alone cannot be stated. The trait is highly polygenic, with the 123-SNP set explaining only 2.71% of variance, implying any single variant's contribution is modest. GTEx v11 eQTL data (953 donors, FDR < 0.05) provides independent functional support linking the locus to LEPROT expression in multiple brain regions. No conflicting studies are present in the provided evidence set, and the relationship between the eQTL signal and the GWAS signal has not been formally colocalized in the provided data.

Tissue-specific expression effects

  • LEPROT: The alternate allele at rs10789181 is associated with reduced expression of LEPROT (leptin receptor overlapping transcript) across eight brain regions. The strongest reductions are observed in the caudate basal ganglia, amygdala, and putamen basal ganglia; reduced expression is also observed in the nucleus accumbens basal ganglia, anterior cingulate cortex (BA24), frontal cortex (BA9), cortex broadly, and hypothalamus, all at FDR < 0.05 in GTEx v11 data from 953 donors GTEx Portal

Lifestyle considerations

No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs10789181 and which gene is it near?

rs10789181 is a common single nucleotide polymorphism (SNP) located in or near the DNAJC6 gene. It was identified as one of 123 independent genetic signals associated with age at first menstrual period in a large meta-analysis of over 182,000 women from 57 studies.

Is rs10789181 linked to the timing of puberty?

Yes. The variant reached genome-wide significance (P < 5 x 10^-8) for association with age at menarche in a meta-analysis of up to 182,416 women of European descent. The 123 variants in this set together explain about 2.71% of the variation in menarche age in independent replication.

What does rs10789181 do to gene expression in the brain?

According to GTEx v11 data from 953 donors, the alternate allele at rs10789181 is linked to reduced expression of LEPROT (leptin receptor overlapping transcript) in eight brain regions, including the hypothalamus, amygdala, caudate, and frontal cortex. These are eQTL associations showing a statistical relationship between the variant and gene activity, not a proven causal mechanism.

Does this variant affect males as well as females?

The primary association with age at menarche is female-specific, but 90 out of 106 menarche-associated loci showed consistent effects on Tanner stage (a measure of physical development) in both boys and girls combined, and 72 of 106 were consistent in boys alone, suggesting the underlying biology influences pubertal timing across sexes.

What is LEPROT and why might its brain expression be relevant here?

LEPROT stands for leptin receptor overlapping transcript. GTEx data shows the alternate allele at rs10789181 reduces LEPROT activity in multiple brain regions, most notably in basal ganglia structures and the hypothalamus, which is a key regulator of puberty and energy balance. The functional consequences of this reduced expression at this specific locus have not been established in the provided studies.