@article{Kramarenko:2026:rs.3.rs-8346032/v1,
author = {Kramarenko, D and Haydarlou, P and Powell, G and Rämö, J and Janan, R and Prince, C and Zimmerman, D and Theotokis, P and Thami, P and Haas, J and Garnier, S and Rühle, F and Poel, E and Schmidt, A and Day, S and Helms, A and Lampert, R and Parikh, V and Ingles, J and Lakdawala, N and Owens, A and Saberi, S and Stendhal, J and Ashley, E and Gray, B and Russell, M and Ryan, T and Rossano, J and Abrams, D and Olivotto, I and Miller, E and Lin, K and Maurizi, N and Argiro, A and Berry, C and Cooper, R and Flett, A and Gardner, R and Greenwood, J and Halliday, B and Hutchings, D and Mahmod, M and McCann, G and Page, S and Peebles, C and Raman, B and Swoboda, P and Varnava, A and Wright, D and Prasad, S and Cook, S and Tayal, U and Buchan, R and Walsh, R and Wilde, A and Meder, B and Charron, P and Goel, A and Amin, A and Ellinor, P and Aragam, K and Tadros, R and Pinto, Y and Ho, C and Watkins, H and Ware, J and Bezzina, C and Jurgens, S},
doi = {rs.3.rs-8346032/v1},
journal = {Res Sq},
title = {Leveraging the shared and opposing genetic mechanisms in the heritable cardiomyopathies.},
url = {http://dx.doi.org/10.21203/rs.3.rs-8346032/v1},
year = {2026}
}

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TY  - JOUR
AB  - 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.
AU  - Kramarenko,D
AU  - Haydarlou,P
AU  - Powell,G
AU  - Rämö,J
AU  - Janan,R
AU  - Prince,C
AU  - Zimmerman,D
AU  - Theotokis,P
AU  - Thami,P
AU  - Haas,J
AU  - Garnier,S
AU  - Rühle,F
AU  - Poel,E
AU  - Schmidt,A
AU  - Day,S
AU  - Helms,A
AU  - Lampert,R
AU  - Parikh,V
AU  - Ingles,J
AU  - Lakdawala,N
AU  - Owens,A
AU  - Saberi,S
AU  - Stendhal,J
AU  - Ashley,E
AU  - Gray,B
AU  - Russell,M
AU  - Ryan,T
AU  - Rossano,J
AU  - Abrams,D
AU  - Olivotto,I
AU  - Miller,E
AU  - Lin,K
AU  - Maurizi,N
AU  - Argiro,A
AU  - Berry,C
AU  - Cooper,R
AU  - Flett,A
AU  - Gardner,R
AU  - Greenwood,J
AU  - Halliday,B
AU  - Hutchings,D
AU  - Mahmod,M
AU  - McCann,G
AU  - Page,S
AU  - Peebles,C
AU  - Raman,B
AU  - Swoboda,P
AU  - Varnava,A
AU  - Wright,D
AU  - Prasad,S
AU  - Cook,S
AU  - Tayal,U
AU  - Buchan,R
AU  - Walsh,R
AU  - Wilde,A
AU  - Meder,B
AU  - Charron,P
AU  - Goel,A
AU  - Amin,A
AU  - Ellinor,P
AU  - Aragam,K
AU  - Tadros,R
AU  - Pinto,Y
AU  - Ho,C
AU  - Watkins,H
AU  - Ware,J
AU  - Bezzina,C
AU  - Jurgens,S
DO  - rs.3.rs-8346032/v1
PY  - 2026///
TI  - Leveraging the shared and opposing genetic mechanisms in the heritable cardiomyopathies.
T2  - Res Sq
UR  - http://dx.doi.org/10.21203/rs.3.rs-8346032/v1
UR  - https://www.ncbi.nlm.nih.gov/pubmed/41646289
ER  - 

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