Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.
Cousminer DL., Berry DJ., Timpson NJ., Ang W., Thiering E., Byrne EM., Taal HR., Huikari V., Bradfield JP., Kerkhof M., Groen-Blokhuis MM., Kreiner-Møller E., Marinelli M., Holst C., Leinonen JT., Perry JRB., Surakka I., Pietiläinen O., Kettunen J., Anttila V., Kaakinen M., Sovio U., Pouta A., Das S., Lagou V., Power C., Prokopenko I., Evans DM., Kemp JP., St Pourcain B., Ring S., Palotie A., Kajantie E., Osmond C., Lehtimäki T., Viikari JS., Kähönen M., Warrington NM., Lye SJ., Palmer LJ., Tiesler CMT., Flexeder C., Montgomery GW., Medland SE., Hofman A., Hakonarson H., Guxens M., Bartels M., Salomaa V., ReproGen Consortium None., Murabito JM., Kaprio J., Sørensen TIA., Ballester F., Bisgaard H., Boomsma DI., Koppelman GH., Grant SFA., Jaddoe VWV., Martin NG., Heinrich J., Pennell CE., Raitakari OT., Eriksson JG., Smith GD., Hyppönen E., Järvelin M-R., McCarthy MI., Ripatti S., Widén E., Early Growth Genetics (EGG) Consortium None.
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.