Department of Cardiovascular Surgery, Division of Experimental Surgery, Institute Insure (Institute for Translational Cardiac Surgery), German Heart Center Munich, Munich, Germany.
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry Munich, Munich, Germany.
J Clin Invest. 2021 Jan 19;131(2). doi: 10.1172/JCI141837.
Genetic factors undoubtedly affect the development of congenital heart disease (CHD) but still remain ill defined. We sought to identify genetic risk factors associated with CHD and to accomplish a functional analysis of SNP-carrying genes. We performed a genome-wide association study (GWAS) of 4034 White patients with CHD and 8486 healthy controls. One SNP on chromosome 5q22.2 reached genome-wide significance across all CHD phenotypes and was also indicative for septal defects. One region on chromosome 20p12.1 pointing to the MACROD2 locus identified 4 highly significant SNPs in patients with transposition of the great arteries (TGA). Three highly significant risk variants on chromosome 17q21.32 within the GOSR2 locus were detected in patients with anomalies of thoracic arteries and veins (ATAV). Genetic variants associated with ATAV are suggested to influence the expression of WNT3, and the variant rs870142 related to septal defects is proposed to influence the expression of MSX1. We analyzed the expression of all 4 genes during cardiac differentiation of human and murine induced pluripotent stem cells in vitro and by single-cell RNA-Seq analyses of developing murine and human hearts. Our data show that MACROD2, GOSR2, WNT3, and MSX1 play an essential functional role in heart development at the embryonic and newborn stages.
遗传因素无疑会影响先天性心脏病（CHD）的发生，但具体机制仍不明确。本研究旨在寻找与 CHD 相关的遗传风险因素，并对携带 SNP 的基因进行功能分析。我们对 4034 名白人 CHD 患者和 8486 名健康对照进行了全基因组关联研究（GWAS）。在所有 CHD 表型中，染色体 5q22.2 上的一个 SNP 达到了全基因组显著水平，并且与间隔缺损也有关。染色体 20p12.1 上指向 MACROD2 基因座的一个区域在大动脉转位（TGA）患者中确定了 4 个高度显著的 SNP。在胸动脉和静脉异常（ATAV）患者中，染色体 17q21.32 上的 GOSR2 基因座内的 3 个高度显著的风险变异也被发现。与 ATAV 相关的遗传变异被认为会影响 WNT3 的表达，与间隔缺损相关的 rs870142 变异则被认为会影响 MSX1 的表达。我们在体外人类和鼠诱导多能干细胞的心脏分化过程中以及通过发育中鼠和人心脏的单细胞 RNA-Seq 分析，分析了这 4 个基因的表达情况。我们的数据表明，MACROD2、GOSR2、WNT3 和 MSX1 在胚胎和新生儿阶段的心脏发育中发挥着重要的功能作用。
