Lardone, M. C., Busch, A. S., Santos, J. L., Miranda, P., Eyheramendy, S., Pereira, A., et al. (2020). A Polygenic Risk Score Suggests Shared Genetic Architecture of Voice Break With Early Markers of Pubertal Onset in Boys. J. Clin. Endocrinol. Metab., 105(3), E349–E357.
Abstract: Context: Voice break, as a landmark of advanced male puberty in genome-wide association studies (GWAS), has revealed that pubertal timing is a highly polygenic trait. Although voice break is easily recorded in large cohorts, it holds quite low precision as a marker of puberty. In contrast, gonadarche and pubarche are early and clinically well-defined measures of puberty onset. Objective: To determine whether a polygenic risk score (PRS) of alleles that confer risk for voice break associates with age at gonadarche (AAG) and age at pubarche (AAP) in Chilean boys. Experimental Design: Longitudinal study. Subjects and Methods: 401 boys from the Growth and Obesity Chilean Cohort Study (n = 1194; 49.2% boys). Main Outcome Measures: Biannual clinical pubertal staging including orchidometry. AAG and AAP were estimated by censoring methods. Genotyping was performed using the Multi-Ethnic Global Array (Illumina). Using GWAS summary statistics from the UK-Biobank, 29 significant and independent single nucleotide polymorphisms associated with age at voice break were extracted. Individual PRS were computed as the sum of risk alleles weighted by the effect size. Results: The PRS was associated with AAG (beta=0.01, P = 0.04) and AAP (beta=0.185, P = 0.0004). In addition, boys within the 20% highest PRS experienced gonadarche and pubarche 0.55 and 0.67 years later than those in the lowest 20%, respectively (P = 0.013 and P = 0.007). Conclusions: Genetic variants identified in large GWAS on age at VB significantly associate with age at testicular growth and pubic hair development, suggesting that these events share a genetic architecture across ethnically distinct populations.
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Vicuna, L., Barrientos, E., Norambuena, T., Alvares, D., Gana, J. C., Leiva-Yamaguchi, V., et al. (2023). New insights from GWAS on BMI-related growth traits in a longitudinal cohort of admixed children with Native American and European ancestry. iScience, 26(2), 106091.
Abstract: Body-mass index (BMI) is a hallmark of adiposity. In contrast with adulthood, the genetic architecture of BMI during childhood is poorly understood. The few genome-wide association studies (GWAS) on children have been performed almost exclusively in Europeans and at single ages. We performed cross-sectional and longitudinal GWAS for BMI-related traits on 904 admixed children with mostly Mapuche Native American and European ancestries. We found regulatory variants of the immune gene HLA-DQB3 strongly associated with BMI at 1.5 – 2.5 years old. A variant in the sex-determining gene DMRT1 was associated with the age at adiposity rebound (Age-AR) in girls (P = 9.8 x 10(-9)). BMI was significantly higher in Mapuche than in Europeans between 5.5 and 16.5 years old. Finally, Ag
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Vicuna, L., Norambuena, T., Miranda, J. P., Pereira, A., Mericq, V., Ongaro, L., et al. (2021). Novel loci and mapuche genetic ancestry are associated with pubertal growth traits in Chilean boys. Hum. Genet., 140(12), 1651–1661.
Abstract: Puberty is a complex developmental process that varies considerably among individuals and populations. Genetic factors explain a large proportion of the variability of several pubertal traits. Recent genome-wide association studies (GWAS) have identified hundreds of variants involved in traits that result from body growth, like adult height. However, they do not capture many genetic loci involved in growth changes over distinct growth phases. Further, such GWAS have been mostly performed in Europeans, but we do not know how these findings relate to other continental populations. In this study, we analyzed the genetic basis of three pubertal traits; namely, peak height velocity (PV), age at PV (APV) and height at APV (HAPV). We analyzed a cohort of 904 admixed Chilean children and adolescents with European and Mapuche Native American ancestries. Height was measured on roughly a 6-month basis from childhood to adolescence between 2006 and 2019. We predict that the difference in HAPV between an European and a Mapuche adolescent is 4.3 cm higher in the European (P = 0.042) and APV is 0.73 years later for the European compared with the Mapuche adolescent on average (P = 0.023). Further, by performing a GWAS on 774, 433 single-nucleotide polymorphisms, we identified a genetic signal harboring 3 linked variants significantly associated with PV in boys (P < 5 x 10(-8)). This signal has never been associated with growth-related traits.
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