Genetic variation of follicle-stimulating hormone action is associated with age at testicular growth in boys

TY - JOUR

T1 - Genetic variation of follicle-stimulating hormone action is associated with age at testicular growth in boys

AU - Busch, Alexander S.

AU - Hagen, Casper P.

AU - Main, Katharina M.

AU - Pereira, Anita

AU - Corvalan, Camila

AU - Almstrup, Kristian

AU - Mericq, Veronica

AU - Juul, Anders

PY - 2017/5

Y1 - 2017/5

N2 - Context: Although genetic factors play a pivotal role inmale pubertal timing, genome-wide association studies have identified only a few loci. Genetic variation of follicle-stimulating hormone (FSH) action affects adult reproductive parameters and female pubertal timing. Objective: To investigate whether genetic variation affecting FSH action is associated with onset of puberty in boys. Design: Cross-sectional and longitudinal study of two cohorts of healthy boys. Setting: This was a population-based study. Patients or Other Participants: Danish (n = 1130) and Chilean (n = 424) boys were followed through puberty and genotyped for FSHB c.-211G>T, FSHR c.-29A>G, and FSHR c.2039>A. Main Outcome Measures: Clinical pubertal staging including orchidometry, anthropometry, and serum gonadotropin levels. Results: Although the cohorts differed markedly (e.g., body composition and genotype frequencies), genetic variation affecting FSH production (FSHB c.-211G>T) was associated with age at pubertal onset, as assessed by testicular enlargement, in both cohorts. The effect appeared further modified by coexistence of genetic variation affecting FSH sensitivity (FSHR c.-29G>A): After correcting for body mass index (BMI), boys with a ligand-receptor variant combination resulting in weak FSH action (i.e., FSHB c.-211GT/TT and FSHR c.-29AA) entered puberty 0.64 years [95%confidence interval (CI), 0.12 to 1.17 years; Denmark] and 0.94 years (95% CI, 0.00 to 1.88 years; Chile) later than boys with the most effective FSH action. Effects explained 1.7% (Denmark) and 1.5% (Chile) of the variance. In addition, BMI z score was negatively associated with pubertal timing (b = 20.35 years in both cohorts), explaining 17.2% (Denmark) and 7.2% (Chile) of the variance. Conclusion: In two ethnically distinct populations, we independently identified an association of two genetic loci with male pubertal timing.

AB - Context: Although genetic factors play a pivotal role inmale pubertal timing, genome-wide association studies have identified only a few loci. Genetic variation of follicle-stimulating hormone (FSH) action affects adult reproductive parameters and female pubertal timing. Objective: To investigate whether genetic variation affecting FSH action is associated with onset of puberty in boys. Design: Cross-sectional and longitudinal study of two cohorts of healthy boys. Setting: This was a population-based study. Patients or Other Participants: Danish (n = 1130) and Chilean (n = 424) boys were followed through puberty and genotyped for FSHB c.-211G>T, FSHR c.-29A>G, and FSHR c.2039>A. Main Outcome Measures: Clinical pubertal staging including orchidometry, anthropometry, and serum gonadotropin levels. Results: Although the cohorts differed markedly (e.g., body composition and genotype frequencies), genetic variation affecting FSH production (FSHB c.-211G>T) was associated with age at pubertal onset, as assessed by testicular enlargement, in both cohorts. The effect appeared further modified by coexistence of genetic variation affecting FSH sensitivity (FSHR c.-29G>A): After correcting for body mass index (BMI), boys with a ligand-receptor variant combination resulting in weak FSH action (i.e., FSHB c.-211GT/TT and FSHR c.-29AA) entered puberty 0.64 years [95%confidence interval (CI), 0.12 to 1.17 years; Denmark] and 0.94 years (95% CI, 0.00 to 1.88 years; Chile) later than boys with the most effective FSH action. Effects explained 1.7% (Denmark) and 1.5% (Chile) of the variance. In addition, BMI z score was negatively associated with pubertal timing (b = 20.35 years in both cohorts), explaining 17.2% (Denmark) and 7.2% (Chile) of the variance. Conclusion: In two ethnically distinct populations, we independently identified an association of two genetic loci with male pubertal timing.

U2 - 10.1210/jc.2016-4013

DO - 10.1210/jc.2016-4013

M3 - Journal article

C2 - 28323923

AN - SCOPUS:85019159053

SN - 0021-972X

VL - 102

SP - 1740

EP - 1749

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 5

ER -