| Title: |
Leveraging the shared and opposing genetic mechanisms in the heritable cardiomyopathies |
| Authors: |
Kramarenko, Daria, R; Umc, Amsterdam; Powell, George, J; Rämö, Joel, T; Janan, Riyad; Prince, Claire; Zimmerman, Dominic, S; Theotokis, Pantazis; Thami, Prisca, K; Haas, Jan; Garnier, Sophie; Rühle, Frank; Poel, Edwin; Schmidt, Amand, F; Helms, Adam; Lampert, Rachel; Parikh, Victoria; Ingles, Jodie; Lakdawala, Neal; Owens, Anjali; Saberi, Sara; Stendhal, John; Ashley, Euan; Gray, Belinda; Russell, Mark, W; Ryan, Thomas, D; Rossano, Joseph, W; Abrams, Dominic; Olivotto, Iacopo; Miller, Erin; Lin, Kimberly; Maurizi, Niccolo; Argiro, Alessia; Berry, Colin; Cooper, Rob; Flett, Andrew, S; Gardner, Roy, S; Greenwood Baker, John; Halliday, Brian, P; Hutchings, David; Mahmod, Masliza; Mccann, Gerry, P; Peebles, Charles; Raman, Betty; Swoboda, Peter; Varnava, Amanda; Wright, David; Cook, Stuart; Buchan, Rachel; Walsh, Roddy; George, St; Wilde, Arthur, a M; Meder, Benjamin; Charron, Philippe; Goel, Anuj; Amin, Ahmad, S; Ellinor, Patrick, T; Aragam, Krishna, G; Tadros, Rafik, K; Pinto, Yigal, M; Ho, Carolyn, Y; Watkins, Hugh; Ware, James, S; Bezzina, Connie, R; Jurgens, Sean, J; Haydarlou, Poeya; Day, Sharlene; Greenwood, John, P; Page, Stephen, P; Prasad, Sanjay; Tayal, Paz |
| Contributors: |
Academic Medical Center - Academisch Medisch Centrum Amsterdam (AMC); Universiteit van Amsterdam = University of Amsterdam (UvA); ANR-10-LABX-0013,GENMED,Medical Genomics(2010); European Project: 101115295,HORIZON-EIC-2022-PATHFINDERCHALLENGES-01,HORIZON-EIC-2022-PATHFINDERCHALLENGES-01,NaV1.5-CARED(2023) |
| Source: |
https://hal.science/hal-05534684 ; 2026. |
| Publisher Information: |
CCSD |
| Publication Year: |
2026 |
| Subject Terms: |
[SDV]Life Sciences [q-bio] |
| Description: |
Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are heart muscle diseases with largely opposing structural and functional phenotypes. Yet, both may lead to the same devastating outcomes of advanced heart failure and life-threatening arrhythmias. Using genome-wide association data from 9,365 DCM cases, 5,900 HCM cases, and over 1.2 million controls, we show that DCM and HCM are largely inversely associated across multiple genomic levels. Modeling both disorders as opposing genetic entities, in case-case GWAS approaches, we identify 100 loci (17 novel) underlying the cardiomyopathy spectrum. Several loci map to potential therapeutic targets (e.g., ADM, CACNA2D2), and polygenic risk scores derived from these data show strong discrimination between DCM and HCM patients in external datasets (AUC 0.78-0.84; AUPRC ~ 0.85). The pervasive opposing associations suggest that cardiomyocyte-directed therapies may often have opposite effects in DCM versus HCM. Nevertheless, a shared-effect analysis reveals a single locus -near the calcium-buffering gene CASQ2 -and also identifies a concordant genomic component associated with cardiometabolic health and extracardiac risk factors. By leveraging the shared and opposing genetic mechanisms of DCM and HCM, our work defines the genomic architecture of major cardiomyopathy subtypes and suggests new directions for therapeutics and precision medicine in heart failure. |
| Document Type: |
report |
| Language: |
English |
| Relation: |
info:eu-repo/grantAgreement//101115295/EU/NaV1.5 regulation fine-tuning as a therapy for cardiac Conduction and Arrhythmic diseases at Risk of suddEn Death/NaV1.5-CARED |
| DOI: |
10.21203/rs.3.rs-8346032 |
| Availability: |
https://hal.science/hal-05534684; https://hal.science/hal-05534684v1/document; https://hal.science/hal-05534684v1/file/v1_covered_2af135af-4906-43bf-bd5d-2fb3b9028f12.pdf; https://doi.org/10.21203/rs.3.rs-8346032 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.DC2917D1 |
| Database: |
BASE |