Genetic determinants of pubertal timing in the general population

Abstract

Puberty is an important developmental stage during which reproductive capacity is attained. The timing of puberty varies greatly among healthy individuals in the general population and is influenced by both genetic and environmental factors. Although genetic variation is known to influence the normal spectrum of pubertal timing, the specific genes involved remain largely unknown. Genetic analyses have identified a number of genes responsible for rare disorders of pubertal timing such as hypogonadotropic hypogonadism and Kallmann syndrome. Recently, the first loci with common variation reproducibly associated with population variation in the timing of puberty were identified at 6q21 in or near LIN28B and at 9q31.2. However, these two loci explain only a small fraction of the genetic contribution to population variation in pubertal timing, suggesting the need to continue to consider other loci and other types of variants. Here we provide an update of the genes implicated in disorders of puberty, discuss genes and pathways that may be involved in the timing of normal puberty, and suggest additional avenues of investigation to identify genetic regulators of puberty in the general population.

Figure 1. Genetic basis of delayed puberty

A paradigm for understanding the genetics of puberty is shown. Some genes underlying the pathogenesis of Kallmann Syndrome (KS) and hypogonadotropic hypogonadism (HH) have been identified and are depicted with each diagnosis; less is known about the genetic basis of Constitutional Delay of Growth and Puberty (CDGP). There is overlap between the three clinical entities as illustrated by the overlapping circles. There is also likely overlap in their genetic bases, as has been reported for FGFR1 (in KS, HH, and CDGP), GNRHR (in HH and possibly CDGP), PROK2 (in KS and HH), PROKR2 (in KS and HH), FGF8 (in KS and HH), and CHD7 (in KS and HH). Thus far, mutations in only GNRHR and FGFR1 have been found in cases of delayed puberty who are members of families with HH or KS but who themselves have no features of the more severe disorders [35,49,50]. Whether genetic variation in these genes plays a role in modulating pubertal timing in the general population (outside of families with HH or KS) is not clear [36,37] and has yet to be proven experimentally. In both KS and HH, approximately 70% of the genetic causes are still unknown. (Please see text for a more detailed discussion of these genes and their roles in these disorders.) Figure modified with permission from Kaminski BA and Palmert MR. Human Puberty: Physiology, Progression, and Genetic Regulat ion of Variation in Onset. In: D Pfaff, A Arnold, A Etgen, S Fahrbach, and R Rubin, editors. Hormones, Brain, and Behavior (2^nd ed). Elsevier Science (USA), San Diego, CA. Copyright Elsevier 2008.

Figure 2. Genetic ancestry and age at menarche

Mean ancestry estimates for each self-reported racial/ethnic group separated by early and late menarche. The “major ethnicity” on the y-axis represents the estimated contribution of the ancestry that has the largest contribution to a given self-reported ethnic group. For African-Americans, major ethnicity is estimated West African ancestry; for Native Hawaiians, major ethnicity is estimated Native Hawaiian ancestry; for Japanese-Americans, major ethnicity is estimated East Asian ancestry; for Latinas, major ethnicity is estimated European ancestry; for whites, major ethnicity is estimated European ancestry. ***p<0.01, **p<0.05, *p<0.1. Figure reproduced with permission from Journal of Clinical Endocrinology and Metabolism 93: 4290–4298. Copyright 2008, The Endocrine Society.