英国伦敦大学学院R. Thomas Lumbers等研究人员合作发现，全基因组关联分析为扩张型心肌病的分子病因提供新的见解。2024年11月21日，《自然—遗传学》杂志在线发表了这项成果。

研究人员开展了一项全基因组关联研究和多性状分析，包括扩张型心肌病（DCM）（14256 个病例）和三种左心室性状（36203 名UK Biobank参与者）。研究鉴定出80个基因组风险位点，并优先确定了62个潜在的效应基因，包括一些与稀有变异型DCM相关的基因（MAP3K7、NEDD4L 和 SSPN）。

通过单核转录组学，研究人员发现了驱动病理发生的细胞状态、生物通路以及细胞内通讯。研究表明，多基因评分能够预测普通人群中的DCM风险，并改变携带稀有DCM变异的个体的外显率。这些发现或可用于设计结合多基因背景的遗传检测策略，同时为DCM的分子病因提供了见解，有助于靶向治疗的开发。

附：英文原文

Title: Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Author: Zheng, Sean L., Henry, Albert, Cannie, Douglas, Lee, Michael, Miller, David, McGurk, Kathryn A., Bond, Isabelle, Xu, Xiao, Issa, Hanane, Francis, Catherine, De Marvao, Antonio, Theotokis, Pantazis I., Buchan, Rachel J., Speed, Doug, Abner, Erik, Adams, Lance, Aragam, Krishna G., rnlv, Johan, Raja, Anna Axelsson, Backman, Joshua D., Baksi, John, Barton, Paul J. R., Biddinger, Kiran J., Boersma, Eric, Brandimarto, Jeffrey, Brunak, Sren, Bundgaard, Henning, Carey, David J., Charron, Philippe, Cook, James P., Cook, Stuart A., Denaxas, Spiros, Deleuze, Jean-Franois, Doney, Alexander S., Elliott, Perry, Erikstrup, Christian, Esko, Tnu, Farber-Eger, Eric H., Finan, Chris, Garnier, Sophie, Ghouse, Jonas, Giedraitis, Vilmantas, Gubjartsson, Daniel F., Haggerty, Christopher M., Halliday, Brian P., Helgadottir, Anna, Hemingway, Harry, Hillege, Hans L., Kardys, Isabella, Lind, Lars, Lindgren, Cecilia M., Lowery, Brandon D., Manisty, Charlotte, Margulies, Kenneth B., Moon, James C., Mordi, Ify R.

Issue&Volume: 2024-11-21

Abstract: Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.

DOI: 10.1038/s41588-024-01952-y

Source: https://www.nature.com/articles/s41588-024-01952-y