The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGF binding protein-3 (IGFBP-3), pregnancy-associated plasma protein A (PAPP-A2), IGF-II and IGFBP-5 in 838 children (3–18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated single nucleotide polymorphisms near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger causal relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.

中文翻译：

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IGF-I 及其结合蛋白的蛋白质 QTL 分析提供了对生长生物学的见解。

生长激素和胰岛素样生长因子 (IGF) 系统是人体生长不可或缺的一部分。全基因组关联研究（GWAS）已经识别出与身高相关的变异，并且位于该通路中基因附近。然而，这些遗传关联的潜在机制尚不清楚。为了研究该途径中基因的调节以及调节影响生长的机制，我们对测量的 IGF-I、IGF 结合蛋白-3 (IGFBP-3)、妊娠相关血浆蛋白 A (IGFBP-3) 的血清蛋白水平进行了 GWAS。来自辛辛那提基因组对照队列的 838 名儿童（3-18 岁）的 PAPP-A2）、IGF-II 和 IGFBP-5。我们鉴定了与IGFBP3和IGFBP5基因附近的蛋白质水平相关的变异，这些变异包含与身高和其他骨骼生长表型相关的多个信号。令人惊讶的是，通过条件分析证实，与这两个基因座的蛋白质水平相关的变异并不与身高相关性共定位。相反，IGFBP3信号（与 IGFBP-3 和 IGF-II 总水平相关）与坐高比 (SHR) 相关。IGFBP5信号（与 IGFBP-5 水平相关）与出生体重共定位。事实上，编码该通路中其他蛋白质的基因附近与身高相关的单核苷酸多态性与血清水平无关，可能排除 PAPP-A2。孟德尔随机化支持测量的血清水平与 SHR（对于 IGFBP-3）和出生体重（对于 IGFBP-5）之间的因果关系比与身高之间的因果关系更强。总之，我们开始表征儿童期 IGF 相关蛋白血清水平的遗传调控。此外，我们的数据强烈表明存在通过IGF相关基因发挥作用的生长调节机制，其作用方式并未反映在测量的相应蛋白质的血清水平中。