rs1129700 (KCTD13/ASPHD1): Puberty Timing Variant
Key takeaways
- rs1129700, in the 16p11.2 region near KCTD13 and ASPHD1, is one of 123 genetic signals linked to age at first menstrual period in a large genome-wide study of up to 182,416 women.
- The 123 genome-wide significant menarche signals together explain about 2.71% of variation in the trait, reflecting a highly polygenic architecture.
- Many of the loci tied to menarche timing also associate with pubertal development in boys, suggesting shared genetic regulation of puberty across sexes.
- The alternate allele at this locus is linked to increased TBX6 expression across multiple body tissues, pointing to a possible regulatory function at this chromosomal region.
Key takeaways
- rs1129700, located in the 16p11.2 chromosomal region near KCTD13 and ASPHD1, is one of 123 genetic signals linked to age at menarche (the age of first menstrual period) identified in a large genome-wide study of up to 182,416 women.
- The 123 genome-wide significant signals for menarche timing together explain about 2.71% of variation in the trait, reflecting a highly polygenic architecture where many variants each contribute a small effect.
- Many of the loci tied to menarche timing also associate with pubertal development in boys, suggesting shared genetic regulation of puberty across sexes.
- The alternate allele at this locus is linked to increased TBX6 expression across multiple body tissues, pointing to a possible regulatory function at this chromosomal region.
What the research says A genome-wide association study (GWAS, a method that scans the genome for variants linked to a trait) of age at menarche, involving up to 182,416 women of European descent from 57 independent studies, identified 123 independent signals at 106 genomic loci reaching genome-wide significance (P<5x10-8); rs1129700 is among the signals from this analysis. In an independent replication sample of 8,689 women, the 123 signals collectively explained 2.71% of variance in age at menarche (P<1x10-20), with 104 of 123 signals showing directionally consistent associations. Gene expression data from the GTEx project (953 donors, FDR<0.05) separately links the alternate allele at this locus to increased expression of TBX6, a gene in the same 16p11.2 region, across eight body tissues. GTEx Portal
Reported associations
- Age at menarche: rs1129700 falls within one of 123 genome-wide significant signals from a GWAS of up to 182,416 European women; the collective set of 123 signals explains approximately 2.71% of trait variance in independent replication (P<1x10-20).
- Pubertal timing across sexes: 90 of the 106 menarche loci showed consistent association directions with Tanner stage (a standardized scale of physical development) in boys and girls combined (binomial sign test P=1.1x10-13), and 72 of 106 showed consistency in boys alone (P=0.0001).
- TBX6 gene expression: The alternate allele at this locus is associated with increased TBX6 expression in eight tissues: spleen, aorta, esophagus muscle layer, sun-exposed skin, non-sun-exposed skin, tibial artery, tibial nerve, and thyroid, based on GTEx eQTL (expression quantitative trait locus) data. GTEx Portal
Evidence quality The menarche GWAS is among the largest studies of its kind, spanning up to 182,416 European women from 57 studies with a strict genome-wide significance threshold (P<5x10-8). Directional replication for 104 of 123 signals in an independent sample of 8,689 women (binomial sign test P=2.2x10-15) supports robustness of the findings at the set level. The study text reviewed here does not provide a variant-specific effect size or confidence interval for rs1129700 individually, so its independent contribution to menarche timing cannot be quantified from these materials alone. The trait architecture is described as highly polygenic, with all autosomal SNPs together estimated to explain 15.8% of menarche variance (S.E. 3.6%, P=2.2x10-6). The GTEx eQTL data (953 donors, FDR<0.05) characterizes a potential gene-regulatory mechanism but does not establish a clinical outcome. No conflicting studies were included in the materials reviewed.
Tissue-specific expression effects
- TBX6: The alternate allele at rs1129700 is associated with increased TBX6 expression across all eight tissues assessed: spleen, aorta, esophagus muscle layer, sun-exposed skin, non-sun-exposed skin, tibial artery, tibial nerve, and thyroid. TBX6 is a distinct gene located within the same 16p11.2 region as KCTD13 and ASPHD1; the GTEx data for this variant covers TBX6 only and does not report eQTL effects on KCTD13 or ASPHD1. GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is rs1129700 associated with?
rs1129700 is associated with age at menarche, the age at which females first experience menstruation. It was identified as one of 123 genome-wide significant signals in a large study of up to 182,416 women of European descent.
What are the KCTD13 and ASPHD1 genes?
KCTD13 and ASPHD1 are genes located in the 16p11.2 chromosomal region near rs1129700. The studies reviewed here do not describe specific functions for these genes in the context of this variant; they are identified as the nearest reference genes to the variant's position.
Does rs1129700 affect gene expression?
Yes. Data from the GTEx project shows that the alternate allele at rs1129700 is associated with increased expression of the TBX6 gene across at least eight body tissues, including skin, thyroid, aorta, and nerve tissue. This is a potential regulatory effect, not a direct health outcome.
Is this variant linked to puberty timing in boys as well as girls?
Research suggests it may be. In the menarche GWAS, 72 of the 106 identified loci showed consistent associations with pubertal stage in boys, and 90 of 106 loci were consistent in boys and girls combined, supporting a shared genetic basis for puberty timing across sexes.
How large is the individual effect of rs1129700 on age at menarche?
A variant-specific effect size for rs1129700 alone is not provided in the study text reviewed here. The full set of 123 genome-wide significant signals accounts for about 2.71% of variation in menarche timing, reflecting a highly polygenic trait where many variants each contribute a small effect.