@article{24be7e53d1ae4eae85f933fd6d8b2063,
title = "Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy",
abstract = "Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for heart transplantation. Many rare genetic variants have been associated with DCM, but common variant studies of the disease have yielded few associated loci. As structural changes in the heart are a defining feature of DCM, we report a genome-wide association study of cardiac magnetic resonance imaging (MRI)-derived left ventricular measurements in 36,041 UK Biobank participants, with replication in 2184 participants from the Multi-Ethnic Study of Atherosclerosis. We identify 45 previously unreported loci associated with cardiac structure and function, many near well-established genes for Mendelian cardiomyopathies. A polygenic score of MRI-derived left ventricular end systolic volume strongly associates with incident DCM in the general population. Even among carriers of TTN truncating mutations, this polygenic score influences the size and function of the human heart. These results further implicate common genetic polymorphisms in the pathogenesis of DCM.",
author = "Pirruccello, {James P.} and Alexander Bick and Minxian Wang and Mark Chaffin and Samuel Friedman and Jie Yao and Xiuqing Guo and Venkatesh, {Bharath Ambale} and Taylor, {Kent D.} and Post, {Wendy S.} and Stephen Rich and Lima, {Joao A.C.} and Rotter, {Jerome I.} and Anthony Philippakis and Lubitz, {Steven A.} and Ellinor, {Patrick T.} and Khera, {Amit V.} and Sekar Kathiresan and Aragam, {Krishna G.}",
note = "Funding Information: This work was conducted using the UK Biobank under application 7089. Whole-genome sequencing for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416.v1.p1) was performed at the Broad Institute (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant-quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1, contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1, contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. MESA is supported by the National Heart, Lung, and Blood Institute (NHLBI) and contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Whole-genome sequencing for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the NHLBI. This work was funded by the National Institutes of Health RO1 HL127564 (to S.K.), the National Human Genome Research Institute of the US National Institutes of Health under award number 5UM1HG008895 (to S.K.), and the Ofer and Shelly Nemirovsky Research Scholar Award from Massachusetts General Hospital (to S.K.). K.G.A. is supported by the American Heart Association Institute for Precision Cardiovascular Medicine (17IFUNP33840012). J.P.P. is supported by the John S. LaDue Memorial Fellowship for Cardiovascular Research. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. P.T.E. is supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, and K24HL105780) and the American Heart Association (18SFRN34110082). Funding Information: J.P.P. and A.B. have minor consulting roles with Maze Therapeutics. A.P. is a Venture Partner at GV, a venture capital group within Alphabet. In that capacity, he makes investments in companies in both the life sciences and data sciences, many of which are cardiovascular in focus. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb/Pfizer and Bayer AG. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases, and has served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. S. K. is an employee of Verve Therapeutics, and holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics. He is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; he has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest, and Medscape; he reports patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41467-020-15823-7",
language = "English (US)",
volume = "11",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}