Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience
2024
Jurgens, Sean J | Ramo, Joel T | Kramarenko, Daria R | Wijdeveld, Leonoor F J M | Haas, Jan | Chaffin, Mark D | Garnier, Sophie | Gaziano, Liam | Weng, Lu-Chen | Lipov, Alex | Zheng, Sean L | Henry, Albert | Huffman, Jennifer E | Challa, Saketh | Ruhle, Frank | Verdugo, Carmen Diaz | Krijger Juarez, Christian | Kany, Shinwan | van Orsouw, Constance A | Biddinger, Kiran | Poel, Edwin | Elliott, Amanda L | Wang, Xin | Francis, Catherine | Ruan, Richard | Koyama, Satoshi | Beekman, Leander | Zimmerman, Dominic S | Deleuze, Jean-Francois | Villard, Eric | Tregouet, David-Alexandre | Isnard, Richard | Boomsma, Dorret I | de Geus, Eco J C | Tadros, Rafik | Pinto, Yigal M | Wilde, Arthur a M | Hottenga, Jouke-Jan | Sinisalo, Juha | Niiranen, Teemu | Walsh, Roddy | Schmidt, Amand F | Choi, Seung Hoan | Chang, Kyong-Mi | Tsao, Philip S | Matthews, Paul M | Ware, James S | Lumbers, R Thomas | van der Crabben, Saskia | Laukkanen, Jari | Palotie, Aarno | Amin, Ahmad S | Charron, Philippe | Meder, Benjamin | Ellinor, Patrick T | Daly, Mark | Aragam, Krishna G | Bezzina, Connie R | Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN) ; Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN) ; CHU Pitié-Salpêtrière [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) | Centre National de Recherche en Génomique Humaine (CNRGH) ; Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) | Laboratoire d'excellence en GENomique MEDicale (GENMED) | Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH) | Bordeaux population health (BPH) ; Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM) | CHU Pitié-Salpêtrière [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) | National Institutes of Health | ANR-10-LABX-0013,GENMED,Medical Genomics(2010)
International audience
Show more [+] Less [-]English. 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.
Show more [+] Less [-]Bibliographic information
This bibliographic record has been provided by Institut national de la recherche agronomique
