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Genetic Meta-Analysis Uncovers Common, Rare Variants Linked to Female Puberty Timing

NEW YORK – An international team has tracked down common and rare variants linked to age at menarche (AAM), a puberty measure that represents the start of menstruation in biologically female individuals. The collection made it possible to put together a polygenic score for early or late puberty, while highlighting factors that overlapped with those involved in menopause timing and other traits or conditions.

"Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty," co-senior and corresponding author John Perry, a researcher affiliated with the University of Cambridge MRC epidemiology unit, and his colleagues wrote in Nature Genetics on Monday, noting that the work further pointed to "body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease."

For their study, the researchers began by doing genome-wide association study meta-analyses involving as many as 799,845 women of European or East Asian ancestry enrolled through five large efforts, including the UK Biobank project and biobanks representing individuals in China, Japan, and Korea.

"While the majority of our sample was European, the inclusion of East Asian ancestry data increased our power to identify homogeneous signals across the two ancestries," the authors wrote, though they cautioned that additional research "including individuals from a broader range of ancestry groups will be required to understand how generalizable our findings are to non-European populations."

The multi-ancestry GWAS meta-analyses highlighted 1,080 AAM-associated loci, which had individual effect sizes that ranged from roughly five days per allele for particularly common variants to around 3.5 months per allele for variants with much smaller minor allele frequency rates.

After validating 862 associations for a subset of 969 signals using data from the Danish Blood Donor Study, the investigators came up with a polygenic score (PGS) that distinguished individuals who were prone to early or delayed puberty. For individuals classified into the lowest tier based on the PGS, for example, they saw an average AAM of 11.49 years old, while individuals in the top tier based on the PGS had an AAM of 14.46 years, on average.

Women at the top and bottom 1 percent of polygenic risk exhibited approximately 11-fold and 14-fold higher risks of delayed and precocious puberty, respectively, the authors reported, adding that "the common variant PGS contributes substantially to risks of extremely early and late puberty timing."

The team brought in quantitative trait locus, gene mapping, enhancer, and other data for a causal gene analysis, identifying candidate causal genes that were analyzed in combination with published RNA-seq-based expression data on migrating gonadotropin-releasing hormone neurons during mouse embryo development.

Based on data for 665 genes with high-confidence AAM associations, the researchers suggested that genes linked to AAM in the GWAS tended to have enhanced expression in embryonic mouse gonadotropin-releasing hormone neurons at mid- to late stages of development — a developmental period previously linked to gonadotropin-releasing hormone neuron integration into a puberty-related hypothalamic neural network.

To unearth rarer genetic variants with more pronounced effects on AAM, meanwhile, the team analyzed exome sequence data for 222,283 UK Biobank participants of European ancestry, identifying half a dozen genes containing predicted pathogenic truncating or missense variants with exome-wide significant links to AAM.

In particular, the investigators flagged rare ZNF483 variants with strong AAM associations that stymied puberty timing predictions achieved using the PRS, when present.

They also described overlap between genes associated with AAM in the exome sequence-based association analysis and those implicated in traits and conditions such as body mass index, adult height, and height/weight measurements at 10 years old.

The team found further ties between AAM, BMI, and menopause in common variant and pathway analyses, which highlighted potential roles for DNA damage and DNA repair processes.

"Together, these insights shed light on mechanisms, including early life weight gain and adiposity, hormone secretion and response, and cellular susceptibility to DNA damage, that potentially explain the widely reported relationships between earlier puberty timing and higher risks of later-life mortality, metabolic disease, and cancer," the authors concluded.