Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience

Sean J. Jurgens; Joel T. Rämö; Daria R. Kramarenko; Leonoor F.J.M. Wijdeveld; Jan Haas; Mark D. Chaffin; Sophie Garnier; Liam Gaziano; Lu Chen Weng; Alex Lipov; Sean L. Zheng; Albert Henry; Jennifer E. Huffman; Saketh Challa; Frank Rühle; Carmen Diaz Verdugo; Christian Krijger Juárez; Shinwan Kany; Constance A. van Orsouw; Kiran Biddinger; Edwin Poel; Amanda L. Elliott; Xin Wang; Catherine Francis; Richard Ruan; Satoshi Koyama; Leander Beekman; Dominic S. Zimmerman; Jean François Deleuze; Eric Villard; David Alexandre Trégouët; Richard Isnard; Dorret I. Boomsma; Eco J.C. de Geus; Rafik Tadros; Yigal M. Pinto; Arthur A.M. Wilde; Jouke Jan Hottenga; Juha Sinisalo; Teemu Niiranen; Roddy Walsh; Amand F. Schmidt; Seung Hoan Choi; Kyong Mi Chang; Philip S. Tsao; Paul M. Matthews; James S. Ware; R. Thomas Lumbers; Saskia van der Crabben; Jari Laukkanen

doi:10.1038/s41588-024-01975-5

Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience

Sean J. Jurgens, Joel T. Rämö, Daria R. Kramarenko, Leonoor F.J.M. Wijdeveld, Jan Haas, Mark D. Chaffin, Sophie Garnier, Liam Gaziano, Lu Chen Weng, Alex Lipov, Sean L. Zheng, Albert Henry, Jennifer E. Huffman, Saketh Challa, Frank Rühle, Carmen Diaz Verdugo, Christian Krijger Juárez, Shinwan Kany, Constance A. van Orsouw, Kiran BiddingerEdwin Poel, Amanda L. Elliott, Xin Wang, Catherine Francis, Richard Ruan, Satoshi Koyama, Leander Beekman, Dominic S. Zimmerman, Jean François Deleuze, Eric Villard, David Alexandre Trégouët, Richard Isnard, Dorret I. Boomsma, Eco J.C. de Geus, Rafik Tadros, Yigal M. Pinto, Arthur A.M. Wilde, Jouke Jan Hottenga, Juha Sinisalo, Teemu Niiranen, Roddy Walsh, Amand F. Schmidt, Seung Hoan Choi, Kyong Mi Chang, Philip S. Tsao, Paul M. Matthews, James S. Ware, R. Thomas Lumbers, Saskia van der Crabben, Jari Laukkanen, , ,

Department of Cardiology

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Abstract

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.

Original language	English
Article number	2254
Pages (from-to)	2636–2645
Number of pages	10
Journal	Nature genetics
Issue number	12
Early online date	21 Nov 2024
DOIs	https://doi.org/10.1038/s41588-024-01975-5
Publication status	Published - 2024

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Jurgens, S. J., Rämö, J. T., Kramarenko, D. R., Wijdeveld, L. F. J. M., Haas, J., Chaffin, M. D., Garnier, S., Gaziano, L., Weng, L. C., Lipov, A., Zheng, S. L., Henry, A., Huffman, J. E., Challa, S., Rühle, F., Verdugo, C. D., Krijger Juárez, C., Kany, S., van Orsouw, C. A. (2024). Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience. Nature genetics, (12), 2636–2645. Article 2254. https://doi.org/10.1038/s41588-024-01975-5

@article{ccf793fb6b18461b9641597c68523ff3,

title = "Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience",

abstract = "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.",

author = "Jurgens, {Sean J.} and R{\"a}m{\"o}, {Joel T.} and Kramarenko, {Daria R.} and Wijdeveld, {Leonoor F.J.M.} and Jan Haas and Chaffin, {Mark D.} and Sophie Garnier and Liam Gaziano and Weng, {Lu Chen} and Alex Lipov and Zheng, {Sean L.} and Albert Henry and Huffman, {Jennifer E.} and Saketh Challa and Frank R{\"u}hle and Verdugo, {Carmen Diaz} and {Krijger Ju{\'a}rez}, Christian and Shinwan Kany and {van Orsouw}, {Constance A.} and Kiran Biddinger and Edwin Poel and Elliott, {Amanda L.} and Xin Wang and Catherine Francis and Richard Ruan and Satoshi Koyama and Leander Beekman and Zimmerman, {Dominic S.} and Deleuze, {Jean Fran{\c c}ois} and Eric Villard and Tr{\'e}gou{\"e}t, {David Alexandre} and Richard Isnard and Boomsma, {Dorret I.} and {de Geus}, {Eco J.C.} and Rafik Tadros and Pinto, {Yigal M.} and Wilde, {Arthur A.M.} and Hottenga, {Jouke Jan} and Juha Sinisalo and Teemu Niiranen and Roddy Walsh and Schmidt, {Amand F.} and Choi, {Seung Hoan} and Chang, {Kyong Mi} and Tsao, {Philip S.} and Matthews, {Paul M.} and Ware, {James S.} and Lumbers, {R. Thomas} and {van der Crabben}, Saskia and Jari Laukkanen",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1038/s41588-024-01975-5",

language = "English",

pages = "2636–2645",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

Jurgens, SJ, Rämö, JT, Kramarenko, DR, Wijdeveld, LFJM, Haas, J, Chaffin, MD, Garnier, S, Gaziano, L, Weng, LC, Lipov, A, Zheng, SL, Henry, A, Huffman, JE, Challa, S, Rühle, F, Verdugo, CD, Krijger Juárez, C, Kany, S, van Orsouw, CA, Biddinger, K, Poel, E, Elliott, AL, Wang, X, Francis, C, Ruan, R, Koyama, S, Beekman, L, Zimmerman, DS, Deleuze, JF, Villard, E, Trégouët, DA, Isnard, R, Boomsma, DI, de Geus, EJC, Tadros, R, Pinto, YM, Wilde, AAM, Hottenga, JJ, Sinisalo, J, Niiranen, T, Walsh, R, Schmidt, AF, Choi, SH, Chang, KM, Tsao, PS, Matthews, PM, Ware, JS, Lumbers, RT, van der Crabben, S, Laukkanen, J 2024, 'Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience', Nature genetics, no. 12, 2254, pp. 2636–2645. https://doi.org/10.1038/s41588-024-01975-5

TY - JOUR

T1 - Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience

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

PY - 2024

Y1 - 2024

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 - http://www.scopus.com/inward/record.url?scp=85210027511&partnerID=8YFLogxK

U2 - 10.1038/s41588-024-01975-5

DO - 10.1038/s41588-024-01975-5

M3 - Letter

AN - SCOPUS:85210027511

SN - 1061-4036

SP - 2636

EP - 2645

JO - Nature genetics

JF - Nature genetics

IS - 12

M1 - 2254

ER -

Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience

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Publisher Correction: Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience (Nature Genetics, (2024), 10.1038/s41588-024-01975-5)

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