Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty

Abstract

Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.

Figure 1.

Menarche-advancing alleles in Tanner stage meta-analysis results. QQ plots for the P-values of AAM loci (16,18) in the female Tanner breast stage meta-analysis, male Tanner genital stage meta-analysis and male and female combined meta-analysis can be seen on the left. On the right, the Tanner analysis effect size is plotted for each menarche-advancing allele against the effect size on the timing of menarche [taken from Elks et al. (16) or Cousminer et al (18)]. β, SE and P-value for each marker are presented in more detail in the Supplementary Material, Table S5.

Figure 2.

BMI-increasing alleles in Tanner stage meta-analysis results. QQ plots for alleles which are associated with BMI (39,40) are presented on the left for the female Tanner breast stage meta-analysis, male Tanner genital stage meta-analysis, and the combined male and female meta-analysis. On the right, scatter plots show the Tanner analysis effect size for BMI-increasing alleles that have also been associated with AAM (16,38). β, SE and P-value for each marker are presented in more detail in Supplementary Material, Table S6.