Sovio Ulla, Bennett Amanda J, Millwood Iona Y, Molitor John, O'Reilly Paul F, Timpson Nicholas J, Kaakinen Marika, Laitinen Jaana, Haukka Jari, Pillas Demetris, Tzoulaki Ioanna, Molitor Jassy, Hoggart Clive, Coin Lachlan J M, Whittaker John, Pouta Anneli, Hartikainen Anna-Liisa, Freimer Nelson B, Widen Elisabeth, Peltonen Leena, Elliott Paul, McCarthy Mark I, Jarvelin Marjo-Riitta
Department of Epidemiology and Public Health, Imperial College London, London, United Kingdom.
PLoS Genet. 2009 Mar;5(3):e1000409. doi: 10.1371/journal.pgen.1000409. Epub 2009 Mar 6.
Recent genome-wide association (GWA) studies have identified dozens of common variants associated with adult height. However, it is unknown how these variants influence height growth during childhood. We derived peak height velocity in infancy (PHV1) and puberty (PHV2) and timing of pubertal height growth spurt from parametric growth curves fitted to longitudinal height growth data to test their association with known height variants. The study consisted of N = 3,538 singletons from the prospective Northern Finland Birth Cohort 1966 with genotype data and frequent height measurements (on average 20 measurements per person) from 0-20 years. Twenty-six of the 48 variants tested associated with adult height (p<0.05, adjusted for sex and principal components) in this sample, all in the same direction as in previous GWA scans. Seven SNPs in or near the genes HHIP, DLEU7, UQCC, SF3B4/SV2A, LCORL, and HIST1H1D associated with PHV1 and five SNPs in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, and DOT1L with PHV2 (p<0.05). We formally tested variants for interaction with age (infancy versus puberty) and found biologically meaningful evidence for an age-dependent effect for the SNP in SOCS2 (p = 0.0030) and for the SNP in HHIP (p = 0.045). We did not have similar prior evidence for the association between height variants and timing of pubertal height growth spurt as we had for PHVs, and none of the associations were statistically significant after correction for multiple testing. The fact that in this sample, less than half of the variants associated with adult height had a measurable effect on PHV1 or PHV2 is likely to reflect limited power to detect these associations in this dataset. Our study is the first genetic association analysis on longitudinal height growth in a prospective cohort from birth to adulthood and gives grounding for future research on the genetic regulation of human height during different periods of growth.
近期的全基因组关联(GWA)研究已鉴定出数十种与成人身高相关的常见变异。然而,尚不清楚这些变异如何影响儿童期的身高增长。我们根据拟合纵向身高增长数据的参数生长曲线,得出婴儿期的身高增长峰值速度(PHV1)和青春期的身高增长峰值速度(PHV2)以及青春期身高突增的时间,以测试它们与已知身高变异的关联。该研究包括来自1966年芬兰北部出生队列的N = 3538名单胎个体,这些个体具有基因型数据,并且从0至20岁期间进行了频繁的身高测量(平均每人20次测量)。在该样本中,所测试的48种变异中有26种与成人身高相关(p<0.05,经性别和主成分校正),所有这些变异与先前GWA扫描中的方向相同。HHIP、DLEU7、UQCC、SF3B4/SV2A、LCORL和HIST1H1D基因内部或附近的7个单核苷酸多态性(SNP)与PHV1相关,而SOCS2、SF3B4/SV2A、C17orf67、CABLES1和DOT1L基因内部或附近的5个SNP与PHV2相关(p<0.05)。我们正式测试了变异与年龄(婴儿期与青春期)的相互作用,发现有生物学意义的证据表明SOCS2基因中的SNP存在年龄依赖性效应(p = 0.0030),HHIP基因中的SNP也存在年龄依赖性效应(p = 0.045)。对于身高变异与青春期身高突增时间之间的关联,我们没有像对PHV那样的先前类似证据,并且在多重检验校正后,没有一种关联具有统计学意义。在该样本中,与成人身高相关的变异中不到一半对PHV1或PHV2有可测量的影响,这一事实可能反映了在该数据集中检测这些关联的能力有限。我们的研究是对从出生到成年的前瞻性队列中的纵向身高增长进行的首次遗传关联分析,为未来关于人类生长不同时期身高的遗传调控研究奠定了基础。
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