Genetic Regulation of Pubertal Timing: Implications for Growth



“What triggers puberty?” was listed by Science in its 125th anniversary issue of July 1, 2005, as one of the 125 big questions pointing to critical information gaps in science. The biological clock mechanism forcing childhood to end has indeed intrigued researchers for decades, but up until now the precise switch controlling the initiation of pubertal development has remained elusive. Since genes regulate a substantial proportion of the population variation, the detection of functional genetic variants influencing pubertal timing can be expected to significantly improve our understanding of the underlying molecular mechanisms. Nevertheless, epidemiological data suggest complex regulation by both genes and environmental factors. Therefore, the identification of the individual mutations is far from a trivial task. Key regulatory genes influencing pubertal development have been identified from genetic studies of monogenic rare disorders of puberty characterized by the lack of pubertal development, e.g., hypogonadotropic hypogonadism (HH). These studies have highlighted several genes crucial for the regulation of GnRH neuron function. Less is known about the genetic architecture influencing the physiologic population variation of pubertal timing. However, the recent advent of genome-wide association mapping has led to a wave of gene discoveries regarding common genetic variants influencing complex traits. The discoveries also include the identification of variants nearby the gene LIN28B, significantly associated with the timing of pubertal growth and maturation. Emerging data imply a critical role for LIN28B in the regulation of human development by showing complex and sex-specific effects influencing multiple aspects of growth. Future large-scale genome-wide association studies of pubertal timing can be anticipated to pinpoint additional loci influencing the trait and thereby also to improve our understanding of the basic mechanisms involved in sexual maturation and growth.


Height Growth Pubertal Development Precocious Puberty GWAS Study Pubertal Timing 



The ratio of the lengths of the second and the fourth digits


Body mass index


Constitutional delay of growth and puberty


Cyclin-dependent kinase 6


Central nervous system


Cut-like homeobox 1


Cytochrome P450


DOT1-like, histone H3 methyltransferase (Saccharomyces cerevisiae)




Estrogen receptor 1




Fibroblast growth factor receptor 1


Fibronectin type III and SPRY domain containing 1-like


Gonadotropin-releasing hormone


Gonadotropin-releasing hormone receptor


KISS1 receptor


Genome-wide association study


Hypogonadotropic hypogonadism


High-mobility group AT-hook 2


Kallmann syndrome 1 sequence


KiSS-1 metastasis suppressor


Linkage disequilibrium




Leptin receptor


MicroRNA let-7


Lin-28 homolog B (C. elegans)




Pregnancy-associated plasma protein A, pappalysin 1


Prokineticin receptor 2


Prokineticin 2


Tumor protein p53


SAM and SH3 domain containing 1


Solute carrier family 44, member 1


Single nucleotide polymorphism


Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan (testican) 1


T-cell acute lymphocytic leukemia 2


Transmembrane protein 38B


Zinc finger protein 462



The author wishes to thank Diana L. Cousminer and Jaakko Leinonen for helpful comments on drafts of this manuscript. Diana L. Cousminer is also gratefully acknowledged for carefully checking and correcting the English language of the manuscript.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Institute for Molecular Medicine Finland (FIMM), University of HelsinkiHelsinkiFinland

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