medwireNews: A meta-analysis of genome-wide association studies, published in Nature, reveals a large number of genetic variants that may contribute to the age at which girls experience menarche.

In total, the single nucleotide polymorphisms (SNPs) identified accounted for 15.8% of the variance in girls’ age at menarche, “indicating a highly polygenic architecture”, report the study authors. The top 123 SNPs found accounted for 2.71% of the variance, compared with 1.31% explained by 42 previously identified SNPs.

The new associations were identified using genetic data from more than 180,000 women, and included only SNPs with a minor allele frequency of at least 1%. The 123 top SNPs were spread across 106 genetic loci, with 11 loci containing more than one SNP that was independently associated with age at menarche. Early-menarche variants overlapped with genes implicated in increased adult body mass index and late-menarche variants were associated with loci linked to increased adult height.

The SNPs did not just contribute to age at puberty in girls. Among 6147 peripubertal girls and 3769 boys, 90 of the 106 loci had the same direction of association (ie, positive or negative) with Tanner stage in both genders, 86 were consistent only in girls and 72 only in boys.

Of the SNPs, 29 were located in or close to genes with potential involvement in hormonal functions, including several linked to disorders of puberty, and a number were also located close to genes encoding nuclear hormone receptors, co-activators or co-repressors. Pathway analysis suggested a role for gamma-aminobutyric acid (GABAB) receptor II signalling in age at menarche, with all nine genes in the pathway containing a possible association.

“Notably, GABAB receptor activation inhibits hypothalamic [gonadotropin-releasing hormone] secretion in animal models”, say the researchers.

They also found that six (4.8%) of the menarche-related SNPs were located in imprinted gene regions. In a press statement, lead study author John Perry (University of Cambridge, UK) explained that “imprinted genes place unequal weight on the influence of either the mother’s or the father’s genes.”

He said: “Our findings imply that in a family, one parent may more profoundly affect puberty timing in their daughters than the other parent.”

The team further studied the six SNPs in imprinted regions using data from 35,377 women with known parental origins of alleles. Two associations were located close to imprinted regions that have been linked to genetically determined growth retardation and precocious puberty, and one was linked to Prader–Willi syndrome. For these associations, only the paternally inherited alleles were linked to age at menarche.

A further association was specific to maternally inherited alleles and the remaining two were not specific to either paternal or maternal inheritance.

By Eleanor McDermid, Senior medwireNews Reporter

Nature 2014; Advance online publication

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