Institute for Molecular Medicine, and Department of Public Health, University of Helsinki, Helsinki, Finland.
Hum Mol Genet. 2013 Jul 1;22(13):2735-47. doi: 10.1093/hmg/ddt104. Epub 2013 Feb 27.
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.
青春期身高突增是儿童生长的一个显著特征,反映了青春期的中枢启动和局部生长因子。尽管人们对潜在的遗传学知之甚少,但青春期的生长变异性与激素依赖性癌症和不良心脏代谢健康的成年风险相关。迄今为止,唯一与青春期身高生长相关的基因 LIN28B 多效性地影响儿童生长、青春期和癌症进展,表明存在共同的潜在机制。为了发现影响青春期身高和生长的遗传位点,并将其置于整体生长和成熟的背景下,我们利用纵向收集的身高测量数据,在 18737 个欧洲样本中进行了全基因组关联荟萃分析。我们在 10 个位点发现了显著的关联(P < 1.67 × 10(-8)),包括 LIN28B。五个与青春期时间有关的位点,都影响生长的多个方面。特别是,一个与 MAPK3 表达相关的新变体,与青春期前生长增加和初潮提前有关。另一个位于 ADCY3-POMC 附近的变体与体重指数增加、青春期生长减少和青春期提前有关。虽然流行病学相关性表明,青春期提前标志着从快速青春期前生长到最终身高降低和成年肥胖的途径,但我们的研究表明,与青春期生长相关的个体位点具有不同的纵向生长模式,可能与流行病学观察不同。总的来说,这项研究揭示了连接青春期身高生长、青春期时间和儿童肥胖的复杂遗传结构的一部分,并提供了新的信息来确定这些特征之间的联系过程。