Chondrocytes are cartilage cells that contribute to long-bone growth and are thus key to understanding height biology. However, our knowledge about epigenetic regulation and gene expression of human chondrocytes is sparse. To fill this gap, Richard et al. profiled chondrocytes sampled from different parts of the developing human skeleton (proximal and distal regions of limb bones) by RNA-seq and ATAC-seq. They then leveraged this transcriptomic and epigenomic atlas to better understand how genetic variants affect human height. First, their analysis highlighted specific genes and pathways that are highly active in bone development. They were also able to nominate transcription factors, including FOXP1, that seem to mediate height heritability. Interestingly, they did not detect significant differences in genetic associations between anatomical sites. Integration with data from genome-wide association studies for height identifies cartilage expression modules that support height as an omnigenic complex trait. Indeed, the authors proposed a general conceptual framework for understanding the genetics of complex traits and apply it to type 2 diabetes. It will be interesting to expand this analytical and modeling approach, including additional datasets that cover different cell types, tissues and developmental timepoints to obtain a more comprehensive picture of the genetic regulatory landscape that underlies height variability.

Original reference: Cell https://doi.org/10.1016/j.cell.2024.10.040 (2024)

软骨细胞是有助于长骨生长的软骨细胞，因此是了解身高生物学的关键。然而，我们对人类软骨细胞的表观遗传调控和基因表达的了解很少。为了填补这一空白，Richard 等人通过 RNA-seq 和 ATAC-seq 分析了从发育中的人类骨骼的不同部分（肢体骨骼的近端和远端区域）取样的软骨细胞。然后，他们利用这个转录组学和表观基因组图谱来更好地了解遗传变异如何影响人类身高。首先，他们的分析突出了在骨骼发育中高度活跃的特定基因和通路。他们还能够提名似乎介导身高遗传性的转录因子，包括 FOXP1。有趣的是，他们没有检测到解剖部位之间遗传关联的显着差异。与来自身高全基因组关联研究的数据整合，确定了支持身高作为全基因复杂特征的软骨表达模块。事实上，作者提出了一个通用的概念框架，用于理解复杂特征的遗传学并将其应用于 2 型糖尿病。扩展这种分析和建模方法将很有趣，包括涵盖不同细胞类型、组织和发育时间点的其他数据集，以获得更全面的身高变异性遗传调控景观图景。

Original reference: Cell https://doi.org/10.1016/j.cell.2024.10.040 (2024)