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, Ärnlöv Johan, Raja Anna Axelsson, Backman Joshua D, Baksi John, Barton Paul J R, Biddinger Kiran J, Boersma Eric, Brandimarto Jeffrey, Brunak Søren, Bundgaard Henning, Carey David J, Charron Philippe, Cook James P, Cook Stuart A, Denaxas Spiros, Deleuze Jean-François, Doney Alexander S, Elliott Perry, Erikstrup Christian, Esko Tõnu, Farber-Eger Eric H, Finan Chris, Garnier Sophie, Ghouse Jonas, Giedraitis Vilmantas, Guðbjartsson 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, Morley Michael P, Morris Andrew D, Morris Andrew P, Morton Lori, Noursadeghi Mahdad, Ostrowski Sisse R, Owens Anjali T, Palmer Colin N A, Pantazis Antonis, Pedersen Ole B V, Prasad Sanjay K, Shekhar Akshay, Smelser Diane T, Srinivasan Sundararajan, Stefansson Kari, Sveinbjörnsson Garðar, Syrris Petros, Tammesoo Mari-Liis, Tayal Upasana, Teder-Laving Maris, Thorgeirsson Guðmundur, Thorsteinsdottir Unnur, Tragante Vinicius, Trégouët David-Alexandre, Treibel Thomas A, Ullum Henrik, Valdes Ana M, van Setten Jessica, van Vugt Marion, Veluchamy Abirami, Verschuren W M Monique, Villard Eric, Yang Yifan, Asselbergs Folkert W, Cappola Thomas P, Dube Marie-Pierre, Dunn Michael E, Ellinor Patrick T, Hingorani Aroon D, Lang Chim C, Samani Nilesh J, Shah Svati H, Smith J Gustav, Vasan Ramachandran S, O'Regan Declan P, Holm Hilma, Noseda Michela, Wells Quinn, Ware James S, Lumbers R Thomas
National Heart and Lung Institute, Imperial College London, London, UK.
MRC Laboratory of Medical Sciences, London, UK.
Nat Genet. 2024 Dec;56(12):2646-2658. doi: 10.1038/s41588-024-01952-y. Epub 2024 Nov 21.
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.
扩张型心肌病（DCM）是心力衰竭和心脏移植的主要原因。我们报告了一项针对DCM（14256例病例）和三个左心室特征（36203名英国生物银行参与者）的全基因组关联研究和多性状分析。我们确定了80个基因组风险位点，并对62个推定的效应基因进行了优先排序，其中包括几个与罕见变异DCM相关的基因（MAP3K7、NEDD4L和SSPN）。通过单核转录组学，我们确定了驱动发病机制的细胞状态、生物学途径和细胞内通讯。我们证明多基因评分可预测普通人群中的DCM，并改变罕见DCM变异携带者的外显率。我们的研究结果可能为纳入多基因背景的基因检测策略设计提供参考。它们还为DCM的分子病因学提供了见解，可能有助于开发靶向治疗方法。
