Hypertension as a Novel Link for Shared Heritability in Age at Menarche and Cardiometabolic Traits

J Clin Endocrinol Metab. 2023 Aug 18;108(9):2389-2399. doi: 10.1210/clinem/dgad104.

Abstract

Context: Extremely early age at menarche, also called precocious puberty, has been associated with various cardiometabolic traits, but their shared heritability remains unclear.

Objectives: This work aimed to identify new shared genetic variants and their pathways for age at menarche and cardiometabolic traits and to investigate the influence of central precocious puberty on childhood cardiometabolic traits.

Methods: Using the conjunction false discovery rate method, this study analyzed genome-wide association study data from the menarche-cardiometabolic traits among 59 655 females of Taiwanese ancestry and systemically investigated pleiotropy between age at menarche and cardiometabolic traits. To support the novel hypertension link, we used the Taiwan Puberty Longitudinal Study (TPLS) to investigate the influence of precocious puberty on childhood cardiometabolic traits.

Results: We discovered 27 novel loci, with an overlap between age at menarche and cardiometabolic traits, including body fat and blood pressure. Among the novel genes discovered, SEC16B, CSK, CYP1A1, FTO, and USB1 are within a protein interaction network with known cardiometabolic genes, including traits for obesity and hypertension. These loci were confirmed through demonstration of significant changes in the methylation or expression levels of neighboring genes. Moreover, the TPLS provided evidence regarding a 2-fold higher risk of early-onset hypertension that occurred in girls with central precocious puberty.

Conclusion: Our study highlights the usefulness of cross-trait analyses for identifying shared etiology between age at menarche and cardiometabolic traits, especially early-onset hypertension. The menarche-related loci may contribute to early-onset hypertension through endocrinological pathways.

Keywords: age at menarche; cardiometabolic diseases; molecular pathways; shared genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
  • Child
  • Female
  • Genome-Wide Association Study
  • Humans
  • Hypertension* / epidemiology
  • Hypertension* / genetics
  • Longitudinal Studies
  • Menarche / genetics
  • Phosphoric Diester Hydrolases
  • Puberty, Precocious* / epidemiology
  • Puberty, Precocious* / genetics

Substances

  • FTO protein, human
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • USB1 protein, human
  • Phosphoric Diester Hydrolases