Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK.
Nature. 2020 Aug;584(7822):589-594. doi: 10.1038/s41586-020-2635-8. Epub 2020 Aug 19.
The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.
人类心脏的内表面覆盖着一层复杂的肌肉束网络，据认为这是胚胎发育的残余物。这些小梁在成年人体内的功能及其遗传结构尚不清楚。在这里，我们使用 UK Biobank 中 18096 名参与者的小梁形态分形分析，进行了一项全基因组关联研究，以调查小梁的图像衍生表型。我们鉴定出 16 个显著的位点，其中包含与血流动力学表型和细胞骨架分支调节相关的基因。通过对人类参与者的生物力学模拟和观察数据的研究，我们证明了小梁形态是心脏性能的重要决定因素。通过与心脏疾病表型的遗传关联研究和孟德尔随机化，我们发现小梁形态与心血管疾病风险之间存在因果关系。这些发现表明心肌小梁在成年人心脏功能中的一个以前未知的作用，确定了调节结构复杂性的保守途径，并揭示了心肌小梁对心血管疾病易感性的影响。
