rs11792861 (TMEM245): Pubertal Timing Variant

Key takeaways

• rs11792861 near TMEM245 is one of 123 genetic variants strongly linked to the age when menstruation begins, identified in a study of over 182,000 women.
• Together, all 123 variants explained about 2.71% of the variation in menarche timing, reflecting how many genes contribute to this trait.
• This locus also associates with broader pubertal timing in both boys and girls, not just menarche in females.
• GTEx data shows this variant increases expression of TMEM245 in skin and fibroblast cells, and boosts nearby gene FRRS1L across multiple tissues.
• Age at menarche as a trait is associated with risks for obesity, type 2 diabetes, heart disease, and breast cancer at the population level.

What the research says A meta-analysis of up to 182,416 women of European descent from 57 studies identified rs11792861 at the TMEM245 locus as one of 123 independent genome-wide significant signals (P less than 5x10^-8) for age at menarche, the age at which a person first menstruates. In an independent replication sample of 8,689 women, the full set of 123 signals together explained 2.71% of the variance in menarche timing, while all autosomal SNPs (gene variants spread across non-sex chromosomes) combined explained up to 15.8% (standard error 3.6%), indicating a highly polygenic trait architecture - one shaped by many variants each with a small effect. Ninety of the 106 menarche loci showed consistent directional associations with Tanner stage (a clinical scale of pubertal development) in both boys and girls combined (binomial sign test P=1.1x10^-13), suggesting that the genetic regulation of pubertal timing is broadly shared across sexes.

Reported associations

• Age at menarche: rs11792861 is one of 123 genome-wide significant independent signals (P less than 5x10^-8) identified in a meta-analysis of up to 182,416 European women from 57 studies.
• Pubertal timing (Tanner stage): The locus is among 90 of 106 menarche loci showing consistent directional associations with Tanner stage in boys and girls combined (binomial sign test P=1.1x10^-13).
• Downstream trait associations (population level): Age at menarche as a trait is reported to be associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer, and all-cause mortality; these reflect associations with the timing trait itself rather than with this specific variant.

Evidence quality The primary evidence for this variant comes from a single large GWAS meta-analysis (up to 182,416 women of European descent across 57 studies) with genome-wide significance (P less than 5x10^-8). Directional consistency for the 123-signal set was evaluated in an independent replication sample of 8,689 women, where 104 of 123 signals showed concordant associations or trends, and 35 reached nominal significance (P less than 0.05). No variant-specific effect size - such as an odds ratio, beta coefficient, or percent variance - for rs11792861 alone is reported in the provided study text; the 2.71% variance figure refers to the combined contribution of all 123 signals, not this variant in isolation. The study population was predominantly European, which limits generalizability to other ancestry groups. Puberty timing is a highly polygenic trait, meaning this variant is one of many contributors each with a small individual effect.

Tissue-specific expression effects

• TMEM245: The alternate allele at rs11792861 is associated with increased expression of TMEM245 in cultured fibroblast cells and sun-exposed lower leg skin GTEx Portal.
• FRRS1L: The alternate allele is associated with increased expression of the nearby gene FRRS1L across multiple tissues, with the strongest effect in thyroid tissue, followed by prostate, sigmoid colon, breast mammary tissue, and esophageal tissues GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.