Expanded genomic analyses for male voice-breaking highlights a shared phenotypic and genetic basis between puberty timing and hair colour

Hollis, Benjamin; Fr, Day; As, Busch; Dj, Thompson; Alg, Soares; Timmers, Paul R. H. J.; Kwong, Alex S. F.; Easton, DF; Joshi, Peter K.; Nj, Timpson; Ong, Ken K; Perry,

doi:10.1101/483933

Cited by 3 publications

(8 citation statements)

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“…Puberty is characterized by the reactivation of the hypothalamic–pituitary–gonadal (HPG) axis after childhood leading to physical changes and sexual maturation. The timing of puberty is linked to a number of later health outcomes, such as lifetime incidence of obesity, type 2 diabetes, hypertension and cancer (Day et al ., 2015b; Hollis et al ., 2018).…”

Section: Introductionmentioning

confidence: 99%

Voice break in boys—temporal relations with other pubertal milestones and likely causal effects of BMI

et al. 2019

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STUDY QUESTION How is timing of voice break related to other male pubertal milestones as well as to BMI? SUMMARY ANSWER We provide a comprehensive temporal analysis of male pubertal milestones, including reproductive hormone dynamics, confirm voice break as a late milestone of male puberty and report a likely causal relationship between higher BMI and earlier age at voice break in men. WHAT IS KNOWN ALREADY Voice break represents a late pubertal milestone and recalled age at voice break is frequently used in epidemiological studies as a measure of puberty. In contrast, clinical studies use mainly testicular enlargement and/or genital tanner stage as the marker of pubertal onset. However, neither correlation of pubertal milestones nor reproductive hormone dynamics have been assessed in detail previously. Further, although BMI and puberty timing are known to be closely linked, cause and effect between these traits are not known. STUDY DESIGN, SIZE, DURATION The study included a population-based mixed cross-sectional and longitudinal cohort (2006–2014, COPENHAGEN Puberty Study) of 730 healthy Danish boys. Data for 55 871 male research participants from the 23andMe study were obtained, including genome-wide single nucleotide polymorphism data and age at voice break. PARTICIPANTS/MATERIALS, SETTING, METHODS We performed a detailed evaluation of pubertal milestones and reproductive hormone levels (study population 1). A Mendelian randomization (MR) approach was used to determine the likely causal link between BMI and timing of voice break (study population 2). MAIN RESULTS AND THE ROLE OF CHANCE Voice break occurred at mean age 13.6 (95% CI: 13.5–13.8) years. At voice break, mean (95% CI) testosterone levels, LH levels and bi-testicular volume were 10.9 (10.0–11.7) nmol/L, 2.4 (2.2–2.5) IU/L and 24 (23–25) mL, respectively. Voice break correlated moderately strongly with timing of male pubertal milestones, including testicular enlargement, gonadarche, pubarche, sweat odor, axillary hair growth and testosterone above limit of detection (r2 range: 0.43–0.61). Timing of all milestones was negatively associated with age-specific BMI (all P ≤ 0.001). MR analyses inferred likely causal effects of higher BMI on earlier voice break in males (−0.35 years/approximate SD, P < 0.001). LIMITATIONS, REASONS FOR CAUTION Participation rate of the population-based cohort was 25%. Further, boys that were followed longitudinally were examined approximately every 6 months limiting the time resolution of pubertal milestones. Using adult BMI as exposure instead of prepubertal BMI in the MR analysis and the known inaccuracies of the testosterone immunoassay at low testosterone levels may be further limitations. WIDER IMPLICATIONS OF THE FINDINGS We provide valuable normative data on the temporal relation of male pubertal milestones. Further, the likely causal relationship between BMI and puberty timing highlights the importance of preventing obesity in childhood. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Danish Agency for Science, Technology and Innovation (09-067 180); Danish Ministry of the Environment, CeHoS (MST-621-00 065); Capital Region of Denmark (R129-A3966); Ministry of Higher Education and Science (DFF-1331-00 113); Innovation Fund Denmark (InnovationsFonden, 14-2013-4); The International Center for Research and Research Training in Endocrine Disrupting Effects of Male Reproduction and Child Health. B.H., F.R.D., J.R.B.P. and K.K.O. are supported by the Medical Research Council (MC_UU_12015/2). The 23andMe study is supported by the National Human Genome Research Institute of the National Institutes of Health (R44HG006981). Members of the 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe. TRIAL REGISTRATION NUMBER NCT01411527

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Section: Introductionmentioning

confidence: 99%

Voice break in boys—temporal relations with other pubertal milestones and likely causal effects of BMI

et al. 2019

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“…We could not find publicly available summary statistics for male pubertal timing. However, Hollis et al [6] tested genetic correlations of male pubertal timing with several of the traits used in this study. The authors also report a genetic correlation of male and female pubertal timing of r g = .683, p<2.6E-213, indicating that genetic correlations of male and female pubertal timing should show substantial agreement.…”

Section: Ethical Approvalmentioning

confidence: 99%

“…MR-studies have demonstrated the causal association of BMI and pubertal timing in both directions, suggesting a causal effect of BMI on pubertal timing and vice versa [4,5]. In a recent paper, a genetic correlation was also found for male pubertal timing and BMI [6].…”

Section: Introductionmentioning

confidence: 97%

“…A recent MR-study has also found likely causal effects of BMI on poor mental health and well-being [11]. Hence, it is not surprising that a recent study investigating 751 genetic correlations of male pubertal timing, found positive genetic correlations with maternal longevity, intelligence, an overall health rating, education and a strong negative genetic correlation with BMI [6].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, a recent study tested genetic correlations of antisocial behavior with age of menarche, but did not find a significant genetic correlation [7]. In a study on male puberty, no significant genetic correlations were found with psychiatric problems [6]. Nonetheless, studies based on Mendelian Randomization [MR] did show a transient effect of age of menarche on mental health [depressive symptoms] [8], but not later in life [9].…”

Section: Introductionmentioning

confidence: 99%

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Shared genetic etiology of age of menarche and socioeconomic variables: No evidence for genetic overlap with psychiatric traits

Steppan

2020

Preprint

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Earlier research has shown observational associations of early pubertal timing and poor mental health. Mendelian randomization (MR) studies demonstrated a transient effect of pubertal timing on mental health during adolescence, but not later in life. MR studies also showed that there is a likely causal association of pubertal timing with life history traits. However, the strongest causal effects and genetic correlations with age of menarche have been found for Body Mass Index (BMI). As high BMI is associated with lower socioeconomic status and with poor mental health, the shared genetic etiology of socioeconomic status, BMI and poor mental health is not yet fully understood. BMI correlates negatively with socioeconomic status and several mental health outcomes. Despite their substantial genetic overlap, the underlying genetic etiology of these phenotypes remains unclear. In this study we applied Linkage Disequilibrium score regression to test genetic correlations of age of menarche with 33 socioeconomic, life history, social interaction, personality and psychiatric traits, and BMI. We further applied spectral decomposition and hierarchical clustering to the genetic correlation matrix. After controlling for multiple testing, we could only identify significant genetic correlations with BMI and three socioeconomic traits (household income, deprivation and parental longevity). The results suggest that genomewide association studies on age of menarche also contain socioeconomic information. Future MR studies aiming to test the unconfounded effect of pubertal timing should make sure that genetic instruments have no pleiotropic effect on socioeconomic variables, or (if possible) also control for socioeconomic status on the observational level.

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Prenatal anxiety, breastfeeding and child growth and puberty: linking evolutionary models with human cohort studies

English

Wright

Ashburn

et al. 2020

Annals of Human Biology

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Background: Stress experienced by mothers during pregnancy can have both immediate and long-term effects on child development, potentially mediated by breastfeeding. Aim: Using a UK birth cohort study, we asked how maternal stress relates to breastfeeding and consequences for growth and puberty onset. Subjects and methods: We analysed data from the Avon Longitudinal Study of Parents and Children, collected via questionnaires and clinic visits (N: 698-8,506). We used reports of prenatal anxiety, breastfeeding, early growth and age at menarche or first voice change. Confounding by maternal age, parity, smoking, education and body mass index (BMI) was considered. Results: Mothers with higher levels of reported anxiety were less likely to breastfeed (Odds ratio (OR): 0.83, 95% confidence interval (CI): 0.71, 0.97). Breastfed infants had slower growth before weaning, although growth differences were unclear thereafter. Being breastfed for more than six months was associated with later puberty onset in females (2.76 months later than non-breastfed; CI: 0.9, 4.63), although the association was attenuated by confounders and BMI (1.51 months, CI: À0.38, 3.40). No association between breastfeeding and puberty onset in males was found. Conclusion: Our studies fit results shown previously, and we consider these in light of evolutionary life history theory while discussing key challenges in such an approach.

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Expanded genomic analyses for male voice-breaking highlights a shared phenotypic and genetic basis between puberty timing and hair colour

Cited by 3 publications

References 34 publications

Voice break in boys—temporal relations with other pubertal milestones and likely causal effects of BMI

Voice break in boys—temporal relations with other pubertal milestones and likely causal effects of BMI

Shared genetic etiology of age of menarche and socioeconomic variables: No evidence for genetic overlap with psychiatric traits

Prenatal anxiety, breastfeeding and child growth and puberty: linking evolutionary models with human cohort studies

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