Differential impact of genetic loci on age at thelarche and menarche in healthy girls

Abstract

Context: Recent genetic studies have identified genetic variants associated with age at pubertal onset. Whereas genome-wide association studies reported associations of several hundred genetic variants with timing of self-reported age at menarche, a recent clinical study focused on genetic variation affecting follicle-stimulating hormone action and clinically determined age at thelarche. The observations appear to be incongruent, as effect sizes varied substantially among the studies. Alternatively, this may point to a differential impact of specific genetic loci on distinct pubertal events. Objective: To investigate whether top-candidate genetic variants exhibit a different impact on timing of thelarche vs menarche, respectively. Design: Cross-sectional and longitudinal study of healthy girls. Setting: Population-based study in the Copenhagen area. Patients or Other Participants: Girls (1478) were followed through puberty and genotyped for FSHB c.2211G>T (rs10835638), FSHR c.229G>A (rs1394205), FSHR c.2039A>G (rs6116), LIN28B (rs7759938), INHA (rs4141153), MKRN3 (rs12148769), TMEM38B (rs10453225), and ZNF483 (rs10980921). Main Outcome Measures: Clinical pubertal staging and anthropometric data. Results: We observed an association of LIN28B (rs7759938) with age at thelarche (P> 0.001, effect size: 0.27 year, 95% confidence interval: 0.12 to 0.42) and age at menarche (P = 0.005, 0.17 year, 0.05 to 0.29). FSHB c.2211G>T (rs10835638) and FSHR c.229G>A (rs1394205) minor allele count was associated with age at thelarche (P = 0.004, 0.19 year, 0.06 to 0.31) but not with age at menarche (P = 0.97; all adjusted for body mass index z scores). Conclusion: Our results indicate a differential impact of specific genetic loci on age at thelarche and menarche in healthy girls.