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Researchers Add to Collection of Variants Associated With Menarche Onset Age

NEW YORK (GenomeWeb) – An international team led by investigators in the UK has tracked down new low-frequency coding variants and common X-linked SNPs that appear to influence the age at which girls begin menstruating — a puberty indicator known as menarche.

As they reported online today in Nature Communications, the researchers brought together directly genotyped and imputed data for nearly 193,000 women of European descent to search for coding- and X-linked variants missed in past studies. Along with low-frequency variants in or around five autosomal genes from energy, signaling, and gene regulatory pathways, their analysis uncovered two common loci on the X chromosome that contribute to menarche onset.

Such findings add another piece to the puberty timing puzzle, the team explained, noting that previous genome-wide association studies have linked age at first menarche to common variants at more than 100 sites in the genome.

"[O]ur findings indicate that, similar to other complex traits, the genetic architecture of puberty timing is likely dominated by the additive effects of hundreds or even thousands of variants, each with relatively small effect," senior authors Ken Ong and John Perry, both based at the University of Cambridge, and their co-authors wrote.

For the current analysis, Ong, Perry, and their colleagues turned their attention to variants that had not yet been closely scrutinized for ties to age at menstruation onset, namely rarer protein-coding variants and variants falling on the female sex chromosome.

The team started with data for 76,657 women profiled at almost 62,000 variants with minor allele frequencies below 5 percent by exome array. When combined with self-reported age-at-menarche data for these women, all of European ancestry, the exome array data pointed to an association involving a rare missense variant in ALMS1.

The apparent ties to ALMS1 are intriguing, the researchers explained, since mutations in that gene can cause a syndrome with symptoms that include early puberty and menstrual problems in females.

The researchers tested the ALMS1 SNP and nearly two-dozen more suspicious loci in samples from another 116,317 European women enrolled for studies done by Decode Genetics and 23andMe to search for still more menarche-related variants.

In the process, they verified the ALMS1 association, demonstrating that each rare allele present at the locus was linked to menarche that's delayed by around three months.

The follow-up tests revealed associations between menarche onset and other rare nonsense or missense mutations, too. For instance, the team's analysis suggested menarche may start more than a year later than usual for those with a rare, early stop-coding variant in a gene called TCAR3.

Missense variants in LAMB2 and TNRC6A were linked to later-than-usual menarche as well, the researchers reported, while a missense change in the PRKAG1 gene turned up in some women who started menstruating when they were slightly younger.

Meanwhile, the team's analysis of genotyped and imputed variants on the X chromosome yielded significant associations between age of menarche onset and SNPs in and around the IGSF1 and FAAH2 genes, which have been implicated in conditions impacting puberty, thyroid patterns, and genital features in males or hormone secretion and ovarian function in females, respectively.

Expression data generated by members of the Genotype-Tissue Expression consortium suggests the autosomal and X-linked genes detected in the current study are highly expressed in ovary and/or brain tissue, the study's authors noted. On the other hand, none of the variants identified seemed to directly regulate gene expression, and each appeared to impact puberty through mechanisms that are independent of body mass index.