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

Sean L. Zheng, Albert Henry, Douglas Cannie, Michael Lee, David Miller, Kathryn A. McGurk, Isabelle Bond, Xiao Xu, Hanane Issa, Catherine Francis, Antonio De Marvao, Pantazis I. Theotokis, Rachel J. Buchan, Doug Speed, Erik Abner, Lance Adams, Krishna G. Aragam, Johan Ärnlöv, Anna Axelsson Raja, Joshua D. BackmanJohn Baksi, Paul J.R. Barton, Kiran J. Biddinger, Eric Boersma, Jeffrey Brandimarto, Søren Brunak, Henning Bundgaard, David J. Carey, Philippe Charron, James P. Cook, Stuart A. Cook, Spiros Denaxas, Jean François Deleuze, Alexander S. Doney, Perry Elliott, Christian Erikstrup, Tõnu Esko, Eric H. Farber-Eger, Chris Finan, Sophie Garnier, Jonas Ghouse, Vilmantas Giedraitis, Daniel F. Guðbjartsson, Christopher M. Haggerty, Brian P. Halliday, Lars Lind, Sisse R. Ostrowski, Ole B.V. Pedersen, Henrik Ullum, Ole B.V. Pedersen, COVIDsortium, DBDS Genomic Consortium, Estonian Biobank Research Team, HERMES Consortium

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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.
OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind56
Udgave nummer12
Sider (fra-til)2646–2658
Antal sider32
ISSN1061-4036
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We acknowledge contributions from the 100,000 Genomes Project, COVIDsortium, DBDS Genomic Consortium, Estonian Biobank and HERMES Consortium. This work was supported by funding from the British Heart Foundation (RE/18/4/34215, FS/IPBSRF/22/27059, FS/15/81/31817, FS/ICRF/21/26019, RG/19/6/34387, BC/F/21/220106, FS/18/65/34186, SP/19/1/34461, SP/17/11/32885, CH/P/23/80008, RE/24/130023), the Medical Research Council (MC_UP_1605/13), Wellcome Trust (107469/Z/15/Z); National Institute for Health Research (NIHR) Imperial College Biomedical Research Centre, NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Sir Jules Thorn Charitable Trust (21JTA), National Heart and Lung Foundation, Royston Centre for Cardiomyopathy Research, Rosetrees Trust, GenMED LABEX, UCL British Heart Foundation Research Accelerator and NIHR University College London Biomedical Research Centre. This research was conducted in part using the UKB resource under application numbers 9922, 15422, 18545, 40616 and 47602 and was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the NIHR and NHS England; the Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. Individual study acknowledgements are reported in Supplementary Information . The views expressed in this work are those of the authors and not necessarily those of the funders. For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) license to any author accepted manuscript version arising from this submission.

Funding Information:
S.L.Z. has acted as a consultant for Health Lumen. A.H. and R.T.L. have received funding from Pfizer Inc. R.T.L. has performed paid consultancy for Health Lumen and Fitfile Ltd. J.S.W. has acted as a consultant for MyoKardia, Pfizer, Foresite Labs and Health Lumen and received institutional support from Bristol Myers Squibb and Pfizer Inc. P.C. has received personal fees for consultancies, outside the present work, for Amicus, Pfizer Inc., Owkin and Bristol Myers Squibb. M.-P.D. declares holding equity in Dalcor Pharmaceuticals, unrelated to this work. The authors who are affiliated with deCODE genetics/Amgen Inc. and Regeneron Pharmaceuticals declare competing financial interests as employees. The other authors declare no competing interests.

Publisher Copyright:
© The Author(s) 2024.

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