TY - JOUR
T1 - Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience
AU - FinnGen
AU - VA Million Veteran Program
AU - HERMES Consortium
AU - Jurgens, Sean J.
AU - Rämö, Joel T.
AU - Kramarenko, Daria R.
AU - Wijdeveld, Leonoor F.J.M.
AU - Haas, Jan
AU - Chaffin, Mark D.
AU - Garnier, Sophie
AU - Gaziano, Liam
AU - Weng, Lu Chen
AU - Lipov, Alex
AU - Zheng, Sean L.
AU - Henry, Albert
AU - Huffman, Jennifer E.
AU - Challa, Saketh
AU - Rühle, Frank
AU - Verdugo, Carmen Diaz
AU - Krijger Juárez, Christian
AU - Kany, Shinwan
AU - van Orsouw, Constance A.
AU - Biddinger, Kiran
AU - Poel, Edwin
AU - Elliott, Amanda L.
AU - Wang, Xin
AU - Francis, Catherine
AU - Ruan, Richard
AU - Koyama, Satoshi
AU - Beekman, Leander
AU - Zimmerman, Dominic S.
AU - Deleuze, Jean François
AU - Villard, Eric
AU - Trégouët, David Alexandre
AU - Isnard, Richard
AU - Boomsma, Dorret I.
AU - de Geus, Eco J.C.
AU - Tadros, Rafik
AU - Pinto, Yigal M.
AU - Wilde, Arthur A.M.
AU - Hottenga, Jouke Jan
AU - Sinisalo, Juha
AU - Niiranen, Teemu
AU - Walsh, Roddy
AU - Schmidt, Amand F.
AU - Choi, Seung Hoan
AU - Chang, Kyong Mi
AU - Tsao, Philip S.
AU - Matthews, Paul M.
AU - Ware, James S.
AU - Lumbers, R. Thomas
AU - van der Crabben, Saskia
AU - Laukkanen, Jari
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly.
AB - Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly.
UR - https://www.scopus.com/pages/publications/85210027511
U2 - 10.1038/s41588-024-01975-5
DO - 10.1038/s41588-024-01975-5
M3 - Letter
C2 - 39572784
AN - SCOPUS:85210027511
SN - 1061-4036
VL - 56
SP - 2636
EP - 2645
JO - Nature Genetics
JF - Nature Genetics
IS - 12
M1 - 2254
ER -