Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity

Abstract

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Figure 1.

Study design. We performed a two-stage study to detect and characterize loci influencing the pubertal phase of childhood growth. Stage 1 consisted of locus mapping using a GWA approach on three related simple measurements of the pubertal growth spurt and joint analysis of discovery and follow-up studies of novel variants for height SDS at age 10 years in girls and 12 years in boys (Analysis I). Validated loci were then characterized using a variety of methods in Stage 2, including genetic characterization (conditioned analysis on previously reported nearby SNPs in low or partial pairwise linkage disequilibrium with pubertal growth signals), functional characterization (eQTL analysis of pubertal growth SNPs on the expression levels of nearby genes and pathway analysis on biological pathways using g:Profiler and MAGENTA), characterization of the growth and maturational effects of the identified loci (on height and BMI across puberty, on the timing of menarche for those signals not previously associated with AAM and on early height from 1 to 4 years for loci that influence the timing of menarche and pubertal growth) and the association between BMI-increasing alleles and total pubertal growth.

Figure 2.

Schematic picture of postnatal height and the three partly correlated GWA phenotypes describing pubertal growth. Childhood and pubertal growth rates at the 3rd, 50th and 97th percentile are shown for girls in the left panel and boys in the right panel. Growth rates during puberty vary as a consequence of variable timing of the growth spurt. The black growth curves illustrate a growth pattern representing the mean timing of the pubertal growth spurt, whereas two SDs early (−2 SD) and late (+2 SD) timing of the pubertal growth spurt are shown in dark versus light orange in girls and dark versus light blue in boys. The three genome-wide analysis strategies are illustrated in the bottom of each panel. Analysis I aims at capturing the take-off phase of the pubertal growth spurt and includes a single height measurement relative to the population mean (height SDS) at age 10 years in girls and 12 years in boys. Analyses II measures the change in relative height between age 8 years and adulthood and targets the total magnitude of pubertal growth. Analysis III, measuring the relative height change between age 14 years and adult, targets the late end of the pubertal spurt in height growth that varies depending on the timing of peak height velocity of the growth spurt.

Figure 3.

Height across multiple growth periods for 10 pubertal growth loci. The effect size of linear regression of height SDS against genotype at six age bins from prepuberty to adulthood was plotted longitudinally across adolescence for males (blue) and females (red). (A) MAPK3 (B) Pubertal growth loci not associated with the timing of menarche are shown for the height-increasing allele. All these variants are also associated with adult stature. (C) Pubertal growth loci associated with pubertal timing, shown for the menarche-advancing allele. These loci show divergent association with prepubertal growth. The x-axis represents age and the y-axis is the effect size (beta) of the association between the indicated allele and relative height at each age. *P < 0.002.

Figure 4.

Loci associated with pubertal height and their overlap with partially correlated phenotypes. The 10 genome-wide significant loci were assessed for their association with the correlated traits adult stature, pubertal timing (AAM) and adiposity (BMI) by examining previously published literature. Additionally, for loci not previously associated with pubertal timing, we queried the leading SNPs in GWA data of AAM by the ReproGen Consortium. All the pubertal growth loci showed pleiotropic associations with one or more related phenotype.