medwireNews: Common genetic variants associated with pubertal timing in the general population contribute strongly to the genetics of constitutional delay of puberty (CDP), but only weakly to idiopathic hypogonadotropic hypogonadism (IHH), research suggests.
Writing in the Journal of Clinical Endocrinology & Metabolism, Yee-Ming Chan (Boston Children’s Hospital, Massachusetts, USA) and co-authors say that their findings “support the hypothesis that the common variant genetics of CDP and IHH are largely distinct.”
They explain that although CDP and IHH “may be indistinguishable on initial presentation,” the two conditions have different prognoses and underlying physiology. Furthermore, the genetic basis for CDP is largely unknown whereas around half of IHH cases are associated with rare genetic variants.
Genome-wide association studies (GWAS) have identified over 400 independent loci associated with pubertal timing in the general population, specifically age at voice-breaking, age at facial hair growth (male pubertal hallmarks) and age at menarche (a female pubertal hallmark).
Chan and colleagues used this GWAS data to calculate polygenic scores (PGS) to estimate the effects of common genetic variants on pubertal timing in people with CDP and IHH relative to control cohorts genotyped on the same platforms. Between-group differences were expressed using Cohen’s d, whereby a value of 0.2 or less indicated a small difference, greater than 0.2 but less than 0.8 represented a moderate difference and a d value of 0.8 or more indicated a large difference between the groups.
They found that the 80 individuals with CDP (67.5% males) had significantly higher PGS for male pubertal hallmarks and age at menarche than the 9621 controls (56.7% male), with Cohen’s d values of 0.85 and 0.67, respectively.
The researchers comment that “the magnitude of the difference […] observed in PGS between CDP cases and controls suggests that common genetic variants are a major contributor to the genetic basis for CDP.”
However, they acknowledge that “not all individuals with CDP exhibited an elevated puberty PGS, and other factors may be contributing to delayed puberty in these individuals.”
The 301 participants (67.8% male) with normosmic IHH also had significantly higher PGS for male pubertal hallmarks than the 1868 controls (55.2% male), but the difference was smaller (d=0.20) than that for CDP and was not statistically significant for age at menarche.
Further analyses among the people with normosmic IHH showed that the enrichment of common genetic variants was specific to participants with no apparent rare-variant cause of IHH.
The study also included 348 participants with Kallmann syndrome (IHH plus anosmia or hyposmia). For these individuals, there was no significant difference relative to controls in PGS for either male pubertal hallmarks or age at menarche.
The authors conclude: “The differential contribution of common genetic variants to CDP vs. IHH suggests a potential clinical application: using polygenic scores to prospectively distinguish CDP from IHH.
“However, despite the large difference in mean PGS between CDP cases and controls, there was substantial overlap in the distribution of PGS’s for cases and controls, limiting prognostic power.”
They suggest: “Future studies using PGS’s for pubertal timing in conjunction with clinical features may improve the ability to predict whether a patient with delayed puberty has CDP or IHH, analogous to efforts to combine PGS with other factors to predict risk of cardiovascular disease, breast cancer, all-cause mortality, and other outcomes.”
By Laura Cowen
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