A Polygenic Risk Score Suggests Shared Genetic Architecture of Voice Break With Early Markers of Pubertal Onset in Boys

María C. Lardone, Alexander S. Busch, José L. Santos, Patricio Miranda, Susana Eyheramendy, Ana Pereira, Anders Juul, Kristian Almstrup, Verónica Mericq

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Context: Voice break, as a landmark of advanced male puberty in genome-wide association studies (GWAS), has revealed that pubertal timing is a highly polygenic trait. Although voice break is easily recorded in large cohorts, it holds quite low precision as a marker of puberty. In contrast, gonadarche and pubarche are early and clinically well-defined measures of puberty onset. Objective: To determine whether a polygenic risk score (PRS) of alleles that confer risk for voice break associates with age at gonadarche (AAG) and age at pubarche (AAP) in Chilean boys. Experimental Design: Longitudinal study. Subjects and Methods: 401 boys from the Growth and Obesity Chilean Cohort Study (n = 1194; 49.2% boys). Main Outcome Measures: Biannual clinical pubertal staging including orchidometry. AAG and AAP were estimated by censoring methods. Genotyping was performed using the Multi-Ethnic Global Array (Illumina). Using GWAS summary statistics from the UK-Biobank, 29 significant and independent single nucleotide polymorphisms associated with age at voice break were extracted. Individual PRS were computed as the sum of risk alleles weighted by the effect size. Results: The PRS was associated with AAG (β=0.01, P = 0.04) and AAP (β=0.185, P = 0.0004). In addition, boys within the 20% highest PRS experienced gonadarche and pubarche 0.55 and 0.67 years later than those in the lowest 20%, respectively (P = 0.013 and P = 0.007). Conclusions: Genetic variants identified in large GWAS on age at VB significantly associate with age at testicular growth and pubic hair development, suggesting that these events share a genetic architecture across ethnically distinct populations.

Original languageEnglish
Article numberdgaa003
JournalJournal of Clinical Endocrinology and Metabolism
Issue number3
StatePublished - 8 Jan 2020


  • GWAS
  • gonadarche
  • male puberty
  • polygenic risk score
  • pubarche


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