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Body Mass Loci among Regions Detected in Meta-Analysis of Menarche Age

By Andrea Anderson

NEW YORK (GenomeWeb News) – Some of the same genetic loci linked to body mass, metabolism, and hormone regulation also appear to influence the age at which girls begin menstruating, according to a meta-analysis appearing online yesterday in Nature Genetics.

"It's been suggested for quite a long time that body weight is linked to puberty," co-senior author Anna Murray, a genetics researcher with the University of Exeter's Peninsula Medical School, told GenomeWeb Daily News. "With genetic studies you can start to look at the causal direction of those links."

Members of ReproGen, an international consortium established to investigate female reproductive traits, compiled data from dozens of genome-wide associations studies involving more than 87,000 women to look for loci involved in the age of menarche, when menstruation begins. In the process, the team uncovered dozens of menarche-associated loci — including 30 loci that were verified in follow-up studies of around 15,000 women.

"We were firstly surprised by the number of genes we've identified," Murray said, noting that the genetic effects detected were unexpectedly clear considering the retrospective nature of the study and the fact that it relied on data from older women who had been asked to recall when they started menstruating.

Menstruation, which coincides with the start of puberty in girls, typically begins between the ages of 11 and 14 years old. Early puberty, on the other hand, has been linked to health problems including breast and endometrial cancer, obesity, heart disease, and type 2 diabetes, the researchers noted. And children who are overweight or obese are more likely to experience early menarche, Murray explained.

Even so, relatively little is known about the genes that influence the age at which menstruation begins. So far, just two loci linked to age of menarche have turned up — one in a LIN28B gene whose homolog controls development-related microRNAs in Caenorhabditis elegans and another in an intergenic region on chromosome 9.

To uncover additional genes involved in menarche timing, the team evaluated data on 87,802 women of European ancestry who had been genotyped with various Affymetrix or Illumina arrays through 32 GWAS performed in the US, the UK, Australia, and Europe.

The researchers imputed additional variants using HapMap data, allowing them to look at roughly 2.5 million autosomal SNPs.

They then looked at how genotype corresponded to individuals' recollections of their menarche age, excluding individuals who said they had started menstruating before the age of nine years old or after the age of 17.

"There may be different genes acting in those earlier and later ages," Murray explained, noting that some members of the team may go back to study individuals who begin menstruating extremely early or late.

The search turned up 945 SNPs at 45 loci that reached genome-wide significance in the discovery group.

By weeding out known or non-independent loci and testing for associations in another 14,731 women from 16 previous studies, the team verified ties between 30 of the loci and age of menarche.

Three of the loci fell in or near hormone-related genes such as RXRG, PCSK2, and INHBA, a gene coding for a sub-unit of the inhibin hormone that's produced in the ovary and found at higher levels once girls go through puberty, Murray explained.

Though inhibin "would be a very good candidate to be involved in female reproduction," she added, this seems to be the first study implicating the hormone in the timing of puberty.

Meanwhile, four loci fell in genomic regions affecting the body mass genes FTO, SEC16B, TRA2B, and TMEM18, while three loci were detected in or around BSX, CRTC1, and MCHR2 — genes involved in energy homeostasis.

Together, the team argued, their findings "show a close link between the genetic regulation of energy homeostasis and pubertal timing and suggest the presence of other diverse pathways."

If so, researchers speculate that it might be possible to curb some cases of early menarche by addressing childhood obesity.

Nevertheless, they also emphasized that more research is needed to understand the interplay between genetics, obesity, and environmental factors in menarche.

"We can't say for sure that it's obesity that's causing the earlier menarche," Murray said, explaining that some genes might be influencing body weight and age of menarche independently. "What our study's saying is that the two processes are heavily interlinked."

Down the road, the team plans to do additional studies aimed at better understanding such relationships, Murray said, both in individuals of European descent and in populations from other parts of the world.

They also intend to home in on some of the other genetic regions identified, including those containing genes with no obvious ties to reproduction, to try to identify causal variants and functional changes influencing menarche.

Such studies are expected to not only provide insights into the biology of female development, Murray explained, but may also offer clues into how early menarche relates to breast cancer and other health risks.

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