Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty

Cousminer, Diana L.; Stergiakouli, Evie; Berry, Diane J.; Ang, Wei; Groen-Blokhuis, Maria M.; Körner, Antje; Siitonen, Niina; Ντάλλα, Ιωάννα; Marinelli, M.; Perry, John R. B.; Kettunen, Johannes; Jansen, Ritsert C.; Surakka, Ida; Timpson, Nicholas J.; Ring, Susan M.; McMahon, George; Power, Chris; Wang, Carol A.; Kähönen, Mika; Viikari, Jorma; Lehtimäki, Terho; Middeldorp, Christel M.; Pol, Hilleke E. Hulshoff; Neef, M.; Weise, Sebastian; Pahkala, Katja; Niinikoski, Harri; Zeggini, Eleftheria; Panoutsopoulou, Kalliope; Bustamante, Mariona; Penninx, Brenda W. J. H.; Murabito, Joanne M.; Torrent, Maties; Dedoussis, George; Kieß, Wieland; Boomsma, Dorret I.; Pennell, Craig E.; Raitakari, Olli T.; Hyppönen, Elina; Smith, George Davey; Ripatti, Samuli; McCarthy, Mark I.; Widén, Elisabeth

doi:10.1093/hmg/ddu150

Cited by 85 publications

(67 citation statements)

References 71 publications

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“…Specific gene loci, LIN28B on chromosome 6 is associated with earlier signs of sexual maturation and tempo of growth in both genders 22 . MKL2 on chromosome 16 is associated with menarcheal timing in girls and pubertal timing in boys, indicating common loci for initiation of puberty between the genders 23. Loci associated with increasing body mass index were also associated with earlier puberty in girls, and either earlier or later pubertal timing in boys, consistent with epidemiological data in body composition and pubertal timing 23…”

Section: Factors Controlling the Timing Of Pubertysupporting

confidence: 78%

Recent advances in the understanding and management of delayed puberty

Wei

Crowne

2015

Arch Dis Child

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Delayed puberty, especially in boys, is a common presentation in paediatrics. Recent advances have improved our understanding of the neuroendocrine, genetic and environmental factors controlling pubertal development, and hence inform the pathophysiology of delayed puberty. The discovery of kisspeptin signalling through its receptor identified neuroendocrine mechanisms controlling the gonadotrophin-releasing hormone (GnRH) pulse generator at the onset of puberty. Genetic mechanisms from single gene mutations to single nucleotide polymorphism associated with delayed puberty are being identified. Environmental factors, including nutritional factors and endocrine disruptors, have also been implicated in changes in secular trends and abnormal timing of puberty. Despite these advances, the key clinical question is to distinguish delayed puberty associated with an underlying pathology or hypogonadism from constitutional delay in growth and puberty, which remains challenging as biochemical tests are not always discriminatory. The diagnostic accuracies of newer investigations, including 36-hour luteinising hormone releasing hormone (LHRH) tests, GnRH-agonist tests, antimullerian hormone and inhibin-B, require further evaluation. Sex hormone replacement remains the main available treatment for delayed puberty, the choice of which is largely dictated by clinical practice and availability of the various sex steroid preparations. Spontaneous reversal of hypogonadism has been reported in boys with idiopathic hypogonadotrophic hypogonadism after a period of sex steroid treatment, highlighting the importance of reassessment at the end of pubertal induction. Novel therapies with a more physiological basis such as gonadotrophins or kisspeptin-agonist are being investigated for the management of hypogonadotrophic hypogonadism. Careful clinical assessment and appreciation of the normal physiology remain the key approach to patients with delayed puberty.

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Section: Factors Controlling the Timing Of Pubertysupporting

confidence: 78%

Recent advances in the understanding and management of delayed puberty

Wei

Crowne

2015

Arch Dis Child

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“…Moreover, even in the absence of genetic variants with sex-specific effects, the study of the genes and pathways identified by GWAS provides an opportunity to uncover new factors that contribute to male-female differences in traits such as growth and the timing of puberty since, for example, these genes and pathways may be modulated by differential sex-steroid exposures or epigenetic mechanisms. Sex-specific effects of the Lin28a/Lin28b/let-7 axis have already been identified in growth patterns in mice and humans (Cousminer, et al 2014; Leinonen et al 2012; Lettre et al 2008; Ong et al 2011; Shinoda et al 2013b; Widen et al 2010). By verifying previously published sex differences in the regulation of body weight in a second animal facility and expanding these observations to include sex-specific effects on pubertal timing, we provide further evidence that the Lin28a/Lin28b/let-7 axis can exert sex-specific effects in mice.…”

Section: Discussionmentioning

confidence: 96%

Sex-specific regulation of weight and puberty by the Lin28/let-7 axis

Corre¹,

Shinoda

Zhu³

et al. 2015

Journal of Endocrinology

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Growth and pubertal timing differ in boys and girls. Variants in/near LIN28B associate with age at menarche (AAM) in genome-wide association studies and some AAM-related variants associate with growth in a sex-specific manner. Sex-specific growth patterns in response to Lin28b perturbation have been detected in mice, and overexpression of Lin28a has been shown to alter pubertal timing in female mice. To investigate further how Lin28a and Lin28b affect growth and puberty in both males and females, we evaluated Lin28b loss-of-function (LOF) mice and Lin28a gain-of-function (GOF) mice. Because both Lin28a and Lin28b can act via the conserved microRNA let-7, we also examined let-7 GOF mice. As reported previously, Lin28b LOF led to lighter body weights only in male mice while Lin28a GOF yielded heavier mice of both sexes. Let-7 GOF mice weighed less than controls, and males were more affected than females. Timing of puberty was assessed by vaginal opening (VO) and preputial separation (PS). Male Lin28b LOF and male let-7 GOF, but not female, mice displayed alteration of pubertal timing, with later PS than controls. In contrast, both male and female Lin28a GOF mice displayed late onset of puberty. Together, these data point toward a complex system of regulation by Lin28a, Lin28b, and let-7, in which Lin28b and let-7 can impact both puberty and growth in a sex-specific manner, raising the possibility that this pathway may contribute to differential regulation of male and female growth and puberty in humans.

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“…The relationship of BMI and onset of puberty may be mediated by several factors, such as leptin and kisspeptin, changes in the bioavailability of sex steroids, and environmental exposures for example to endocrine-disrupting chemicals. Recently there have been genome-wide meta-analyses examining onset of puberty and anthropometric traits, and they may provide insight into the relationships of BMI, height velocity, and pubertal timing [85, 86]. Newer fields of investigation include examination of epigenetic modification [87].…”

Section: Obesity and Pubertal Onset And Progressionmentioning

confidence: 99%

Putative Effects of Obesity on Linear Growth and Puberty

Shalitin

Kieß²

2017

Horm Res Paediatr

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Childhood obesity is a major public health problem that has grown to epidemic proportions throughout the world. Obesity is influenced by genetic and environmental factors. The nutritional status plays an important role in growth and body weight regulation. Excess adiposity during childhood can affect the process of growth and puberty. Obese children are frequently tall for their age, with accelerated epiphyseal growth plate maturation despite low growth hormone levels. Several regulatory hormones may affect the process of linear growth in the constellation of obesity, as high levels of insulin and leptin are observed in obese children. Leptin can act as a skeletal growth factor, with a direct effect on skeletal growth centers. The finding that overweight children, especially girls, tend to mature earlier than lean children has led to the hypothesis that the degree of body fatness may trigger the neuroendocrine events that lead to the onset of puberty. Leptin receptors have been identified in the hypothalamus, as well as in gonadotrope cells, ovarian follicular cells, and Leydig cells. The increased leptin and androgen levels seen in obese children may be implicated in their earlier onset of puberty and accelerated pubertal growth. This review is focused on the interaction between childhood obesity and growth and pubertal processes.

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Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty

Cited by 85 publications

References 71 publications

Recent advances in the understanding and management of delayed puberty

Recent advances in the understanding and management of delayed puberty

Sex-specific regulation of weight and puberty by the Lin28/let-7 axis

Putative Effects of Obesity on Linear Growth and Puberty

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