scholarly journals Genomic analyses for age at menarche identify 389 independent signals and indicate BMI-independent effects of puberty timing on cancer susceptibility

2016 ◽  
Author(s):  
Felix R. Day ◽  
Deborah J. Thompson ◽  
Hannes Helgason ◽  
Daniel I. Chasman ◽  
Hilary Finucane ◽  
...  
Keyword(s):  
Rare Variants ◽  
Cancer Susceptibility ◽  
Pubertal Development ◽  
Genetic Regulation ◽  
Age At Menarche ◽  
Cancer Risks ◽  
Early Puberty ◽  
Opposite Pattern ◽  
Timing Of Puberty ◽  
Independent Effects

AbstractThe timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P<5×10−8) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.

scholarly journals Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty

2017 ◽  
Vol 103 (2) ◽  
pp. 649-659 ◽  
Author(s):  
Sasha R Howard ◽  
Leonardo Guasti ◽  
Ariel Poliandri ◽  
Alessia David ◽  
Claudia P Cabrera ◽  
...  
Keyword(s):  
Body Mass ◽  
Rare Variants ◽  
Association Studies ◽  
Delayed Puberty ◽  
Age At Menarche ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Whole Exome ◽  
Timing Of Puberty

Abstract Context Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity–associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/− mice. Results We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/− mice displayed a significantly delayed timing of pubertal onset (P &lt; 0.05). Conclusions Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP.

scholarly journals Etiology of Increased Referrals for Evaluation of Early Puberty in a Tertiary Care Center in Turkey: True Precocious Puberty, Obesity, or Parental Anxiety and Lack of Knowledge?

2021 ◽  
Vol 8 ◽  
pp. 2333794X2110090
Author(s):  
Ayse Pinar Cemeroglu ◽  
Damlanur Kaval ◽  
Ozan Ozcan
Keyword(s):  
Precocious Puberty ◽  
Care Center ◽  
Pubertal Development ◽  
Tertiary Care ◽  
Parental Anxiety ◽  
Adrenal Hyperplasia ◽  
Pediatric Endocrinology ◽  
Early Puberty ◽  
Classic Congenital Adrenal Hyperplasia ◽  
Timing Of Puberty

There has been a global increase in pediatric endocrinology referrals for the concerns of early puberty. The objective of this study was to determine the reasons behind this increase. A retrospective cross-sectional study was designed to analyze the clinical characteristics of patients seen for the concerns of early puberty in pediatric endocrinology clinic of a tertiary care center (Study A). Additionally, a prospective questionnaire study was designed to assess the knowledge and concerns of the mothers regarding the timing of puberty in girls (Study B). In study A, of the 305 girls, 42.9% were overweight/obese, 68.5% either had normal pubertal development for age or were prepubertal, 1 had non-classic congenital adrenal hyperplasia, and 2 had central precocious puberty. Of the 36 boys, 56% were overweight/obese, 64% either had normal pubertal development for age or were prepubertal, and 1 had non-classic congenital adrenal hyperplasia. In study B, 95% of the participants thought the girls have been developing earlier, over 10% considered the first sign of puberty to be normal after the age 14 years and 12.4% considered menarche to be normal after age 14 years. The common sources of anxiety for the participants regarding the earlier timing of puberty were psychosocial issues and short final height. In conclusion, many parents had wrong beliefs/information about the normal timing of puberty and were concerned about precocious puberty in girls. Education of parents about the normal timing of puberty may help avoiding unnecessary referrals, parental anxiety, and financial burden to the society.

Timing of puberty and synchronization of seasonal rhythms by simulated natural photoperiods in female Siberian hamsters

2007 ◽  
Vol 293 (1) ◽  
pp. R413-R420 ◽  
Author(s):  
Matthew P. Butler ◽  
Justin J. Trumbull ◽  
Kevin W. Turner ◽  
Irving Zucker
Keyword(s):  
Pubertal Development ◽  
Somatic Growth ◽  
Life History Trait ◽  
Delayed Puberty ◽  
Summer Solstice ◽  
Early Puberty ◽  
Seasonal Rhythms ◽  
Siberian Hamsters ◽  
Natural Photoperiod ◽  
Timing Of Puberty

The timing of puberty is a critical life history trait of short-lived species; spring-born individuals mature rapidly and breed in the season of birth, whereas young born in mid- to late summer delay puberty until the next spring. The cues that govern the transition from rapid to delayed maturation in natural populations remain unknown. To identify ecologically relevant photoperiod cues that control timing of puberty, we monitored nine cohorts of female Siberian hamsters ( Phodopus sungorus) born every 2 wk from 4 wk before to 12 wk after the summer solstice in a simulated natural photoperiod (SNP). Hamsters born by the summer solstice underwent rapid somatic growth and achieved puberty that summer; among females born 2–4 wk after the solstice, some delayed puberty by many weeks, whereas others manifested early puberty. Hamsters born 6 or more weeks after the solstice generally delayed puberty until the following spring. The transition from accelerated to delayed pubertal development in the SNP occurred at day lengths that induce early puberty when presented as static photoperiods. Despite differences in timing of birth and timing of puberty, fall and subsequent spring seasonal events occurred at similar calendar dates in all cohorts. We found no evidence that prenatal photoperiod history influenced postnatal development of female hamsters. Considered together with a parallel study on males, the present findings point to sex differences in responsiveness to natural photoperiod variations. In both sexes, incrementally changing photoperiods exert a strong organizing effect on seasonal rhythms.

scholarly journals Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype

2021 ◽  
pp. jmedgenet-2021-107747
Author(s):  
Riku Katainen ◽  
Iikki Donner ◽  
Maritta Räisänen ◽  
Davide Berta ◽  
Anna Kuosmanen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rare Variants ◽  
Cancer Susceptibility ◽  
Histone Demethylase ◽  
Interaction Partner ◽  
Transcription Regulator ◽  
H3k9 Trimethylation ◽  
Mutation Carriers ◽  
The Family ◽  
Project Data

BackgroundGenes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types.MethodsWe used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects.ResultsA novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers.ConclusionsThe apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.

scholarly journals Growth and puberty in a prospective cohort of patients with sickle-cell anaemia: an assessment over ten years abstract

2017 ◽  
Vol 27 (1) ◽  
pp. 91 ◽  
Author(s):  
Ingrid Cristiane Pereira Gomes ◽  
Hugo Nivaldo Melo ◽  
Suyaluane Italla Amana Melo ◽  
Nelmo Vasconcelos de Menezes ◽  
Tulio Vinicius Paes Dantas ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
Pubertal Development ◽  
Hereditary Diseases ◽  
Control Group ◽  
Age At Menarche ◽  
Prospective Longitudinal Study ◽  
Cellular Expression ◽  
Z Scores ◽  
Prospective Longitudinal

Introduction: Hereditary haemoglobinopathies are the most common group of monogenic hereditary diseases in the world. Erythrocytes in sickle form, cellular expression of polymerization of deoxygenated HbS, cause intermittent vascular obstruction, leading to tissue ischaemia and consequent chronic damage in organs and endocrine glands. Objective: The evaluation of the growth pattern and pubertal development of a group of patients with sickle-cell anaemia (SCA) from childhood to adulthood. Method: Thirty patients with SCA between the ages of 10 and 23 years were evaluated in a prospective longitudinal study at three points in time (Te1: 2005; Te2: 2010 and Te3: 2015) and compared with controls. Anthropometric, pubertal and hormonal evaluations were carried out. Age- and gender-specific Z-scores for weight, height and BMI (body mass index) were calculated according to the reference growth standards. Results: Thirty patients with SCA (mean age = 13.93 years) were evaluated at Te1 and 26 patients (mean age = 25.08 years) at Te3. The SCA group lower showed Z-scores for weight (p = 0.0002), height (p = 0.0184) and BMI (p = 0.0011) than the control group at Te1. At Te3, there was no difference in height, but weight (p = <0.0001) and BMI (p = <0.0001) were lower in the SCA group. Men showed greater weight commitment than women at the three study times (Te1: p = 0.0340, Te2: p = 0.0426 and Te3: p = 0.0387) and lower BMI in Te3 (p = 0.0155) in the SCA group. There was a significant increase in weight when comparing Te1 with Te3 (p = 0.0009) and in height when comparing Te1 with Te2 (p = 0.0292) and with Te3 (p = 0.0003) in the SCA group. There was a significant increase in weight when comparing Te1 and Te3 (p = 0.0009) and in height when comparing Te1 and Te2 (p = 0.0292) and Te3 (p = 0.0003) in the SCA group. At Te1, 14 cases and 2 controls were prepubertal. Bone age was delayed in 12 patients. Age at menarche was delayed and lower in the SCA group (mean = 15 years). Five patients had gestated, but no patient had experienced fatherhood. At Te1, TSH levels were higher (p = 0.0080) and T3 levels were lower (p = 0.0020) in the SCA group. At Te3, LH and FSH levels were higher in men with SCA (p = 0.0014; p; 0.0002). IGF-I levels were lower in cases both at Te1 (p = 0.0002) and at Te3 (p = 0.0032). Conclusions: Patients with SCA showed growth impairment and pubertal delay compared with healthy controls. However, albeit belatedly, they reached normal sexual maturation and height in adulthood. Women with SCA showed no fertility problems. The findings highlight the need to investigate the intention of paternity and fertility among men with SCA.

scholarly journals Age at menarche in urban school-going girls: association between socio-economic status, BMI and physical activity

2021 ◽  
Vol 8 (2) ◽  
pp. 666
Author(s):  
Amrita Behel ◽  
Leena Raje
Keyword(s):  
Physical Activity ◽  
Socioeconomic Status ◽  
Disease Risk ◽  
Age Of Onset ◽  
Economic Status ◽  
Pubertal Development ◽  
Age At Menarche ◽  
Older Children ◽  
Activity Data ◽  
Genetic And Environmental Factors

Background: Menarche, one of the most reliable markers of pubertal maturity, is a result of a complex interplay between genetic and environmental factors. Since accelerated pubertal development is an important determinant of prognostic disease risk, especially in developing countries, attention must be focused on this important public health aspect.  Methods: Total 200 school-going girls aged between 10-15 years studying in municipal, public-funded and private schools in Mumbai were included in the study based on the inclusion criteria of having attained menarche only in the last three months. Sociodemographic and anthropometric details were collected using a structured schedule and physical activity data was collected using the physical activity questionnaire for older children and adolescents.Results: Socioeconomic status and family size were found to significantly influence the age of onset of menarche (p<0.001). Anthropometric indices of height, weight and BMI were found to have significant negative correlations indicating that taller, heavier girls reached menarche earlier than their shorter and lighter peers (p<0.000). Level of physical activity was also found to be an important contributing factor to age at menarche such that a higher level of physical activity was observed in girls with higher mean menarcheal age (p<0.000).  Conclusions: Age at menarche was found to be influenced by factors such as socioeconomic status, BMI and physical activity.   

Timing of pubertal development and midlife blood pressure in men and women: A Mendelian randomization study

2021 ◽  
Author(s):  
Io Ieong Chan ◽  
Man Ki Kwok ◽  
C Mary Schooling
Keyword(s):  
Blood Pressure ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Pubertal Development ◽  
Sensitivity Analyses ◽  
Age At Menarche ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Pubertal Maturation ◽  
Pubertal Growth

Abstract Introduction Observational studies suggest earlier puberty is associated with higher adulthood blood pressure (BP), but these findings have not been replicated using Mendelian randomization (MR). We examined this question sex-specifically using larger genome-wide association studies (GWAS) with more extensive measures of pubertal timing. Methods We obtained genetic instruments proxying pubertal maturation (age at menarche (AAM) or voice breaking (AVB)) from the largest published GWAS. We applied them to summary sex-specific genetic associations with systolic and diastolic BP z-scores, and self-reported hypertension in women (n=194174) and men (n=167020) from the UK Biobank, using inverse-variance weighting meta-analysis. We conducted sensitivity analyses using other MR methods, including multivariable MR adjusted for childhood obesity proxied by body mass index (BMI). We used late pubertal growth as a validation outcome. Results AAM (beta per one-year later = -0.030 [95% confidence interval (CI) -0.055, -0.005] and AVB (beta -0.058 [95% CI -0.100, -0.015]) were inversely associated with systolic BP independent of childhood BMI, as were diastolic BP (-0.035 [95% CI -0.060, -0.009] for AAM and -0.046 [95% CI -0.089, -0.004] for AVB) and self-reported hypertension (odds ratios 0.89 [95% CI 0.84, 0.95] for AAM and 0.87 [95% CI 0.79, 0.96] for AVB). AAM and AVB were positively associated with late pubertal growth, as expected. The results were robust to sensitivity analysis using other MR methods. Conclusion Timing of pubertal maturation was associated with adulthood BP independent of childhood BMI, highlighting the role of pubertal maturation timing in midlife BP.

scholarly journals Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

2017 ◽  
Vol 35 (20) ◽  
pp. 2240-2250 ◽  
Author(s):  
Julie Lecarpentier ◽  
Valentina Silvestri ◽  
Karoline B. Kuchenbaecker ◽  
Daniel Barrowdale ◽  
Joe Dennis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Cancer Susceptibility ◽  
Prostate Cancer Risk ◽  
Risk Scores ◽  
Cancer Risks ◽  
Prostate Cancer Susceptibility ◽  
Common Genetic Variants ◽  
Breast And Prostate Cancer ◽  
Male Carriers

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated—for the first time to our knowledge—associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10−6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10−9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

scholarly journals Heritability of Testosterone Levels in 12-Year-Old Twins and Its Relation to Pubertal Development

2006 ◽  
Vol 9 (4) ◽  
pp. 558-565 ◽  
Author(s):  
Rosa A. Hoekstra ◽  
Meike Bartels ◽  
Dorret I. Boomsma
Keyword(s):  
Pubertal Development ◽  
Environmental Influences ◽  
Pubic Hair ◽  
Self Report ◽  
Early Puberty ◽  
Salivary Testosterone ◽  
Testosterone Levels ◽  
Genital Development ◽  
Opposite Sex ◽  
Hair Development

AbstractThe aim of this study was to estimate the heritability of variation in testosterone levels in 12-year-old children, and to explore the overlap in genetic and environmental influences on circulating testosterone levels and androgen-dependent pubertal development. Midday salivary testosterone samples were collected on 2 consecutive days in a sample of 183 unselected twin pairs. Androgen-induced pubertal development was assessed using self-report Tanner scales of pubic hair development (boys and girls) and genital development (boys). A significant contribution of genetic effects to the variance in testosterone levels was found. Heritability was approximately 50% in both boys and girls. The remaining proportion of the variance in testosterone levels could be explained by nonshared environmental influences. The relatively high correlation between testosterone levels of opposite-sex dizygotic twins suggests that sex differences in genes influencing variation in testosterone levels have not yet developed in preand early puberty. Variance in pubertal development was explained by a large genetic component, moderate shared environmental influences, and a small nonshared environmental effect. Testosterone levels correlated moderately (r = .31) with pubertal development; the covariance between testosterone levels and pubertal development was entirely accounted for by genetic influences.

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