Main Text
Human growth in height is a multifaceted process including periods of accelerated and decelerated growth velocities. The postnatal growth trajectory can be conceptualized as consisting of three partially overlapping phases of growth: infant growth characterized by rapidly declining growth velocities, slowly decelerating childhood growth, and the pubertal height growth spurt.1 Genes are estimated to account for up to 60%–80% of the within-population variation of overall height growth.2,3 Although the individual genes still remain largely unknown, epidemiological studies propose partly overlapping genetic regulation covering multiple aspects of growth. For example, a longitudinal study of Swedish male twins suggested that a large proportion of the genes affecting postnatal growth in height are the same or are closely linked throughout the whole growth period.3 Furthermore, a significant proportion of shared genes is thought to account for the correlation between increased prepubertal body mass index and the timing of pubertal growth and maturation.4 Thus far, there have been no genome-wide association studies (GWAS) specifically targeting childhood height growth, whereas there have been many recent large-scale association studies successfully identifying loci influencing both body size and pubertal timing. Although there are as many as 47 verified hits influencing final stature,2,5 11 loci influencing adult body mass index,6–8 and 2 loci influencing age at menarche,9–12 these findings explain only a marginal proportion of the overall variance of each trait. Additionally, we know very little about how these loci may influence longitudinal growth.

To elucidate the genetic framework influencing height growth, we utilized the unique resource of longitudinal childhood height data available in Finnish cohorts.13–19 We chose pubertal growth as the primary mapping target for many reasons. Importantly, this growth phase regulates final height, accounting for as much as 15%–20% of adult stature.20,21 Furthermore, most aspects of this growth period are highly heritable.3,22,23 Finally, the phenotypic variation is very large, with as much within-sex variation in timing as 4 yrs.24 The design of our study is presented in Figure 1. Altogether, three different Finnish population cohorts with longitudinal height data collected at different time points during childhood and adulthood, in addition to a fourth cohort with data on adult height, were included. A precise assessment of the pubertal growth spurt requires very frequent height measurements spanning a large age range, data which typically are not readily obtained in an epidemiological setting. Therefore, we monitored this growth phase with a simple and robust measurement capturing growth during late adolescence, the increase in height between age 14 and adulthood. This approach allowed us to maximize the number of subjects available for genome-wide association mapping, thereby also increasing the statistical power. A similar measurement, i.e., the change in relative height between age 12 and adulthood in females and between age 14 and adulthood in males, has previously been shown to correlate strongly with the timing of the pubertal growth spurt.25 Thus, our study design primarily facilitated the detection of loci influencing the timing of the pubertal growth spurt. Moreover, the availability of longitudinal data on childhood height enabled the exploration of putative shared genetic effects influencing multiple periods of postnatal height growth.