Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Sean L. Zheng; Albert Henry; Douglas Cannie; Michael Lee; David Miller; Kathryn A. McGurk; Isabelle Bond; Xiao Xu; Hanane Issa; Catherine Francis; Antonio De Marvao; Pantazis I. Theotokis; Rachel J. Buchan; Doug Speed; Erik Abner; Lance Adams; Krishna G. Aragam; Johan Ärnlöv; Anna Axelsson Raja; Joshua D. Backman; John Baksi; Paul J.R. Barton; Kiran J. Biddinger; Eric Boersma; Jeffrey Brandimarto; Søren Brunak; Henning Bundgaard; David J. Carey; Philippe Charron; James P. Cook; Stuart A. Cook; Spiros Denaxas; Jean François Deleuze; Alexander S. Doney; Perry Elliott; Christian Erikstrup; Tõnu Esko; Eric H. Farber-Eger; Chris Finan; Sophie Garnier; Jonas Ghouse; Vilmantas Giedraitis; Daniel F. Guðbjartsson; Vinicius Tragante; Jessica van Setten; Marion van Vugt; W. M.Monique Verschuren; Marion van Vugt; Folkert W. Asselbergs

doi:10.1038/s41588-024-01952-y

Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Sean L. Zheng, Albert Henry, Douglas Cannie, Michael Lee, David Miller, Kathryn A. McGurk, Isabelle Bond, Xiao Xu, Hanane Issa, Catherine Francis, Antonio De Marvao, Pantazis I. Theotokis, Rachel J. Buchan, Doug Speed, Erik Abner, Lance Adams, Krishna G. Aragam, Johan Ärnlöv, Anna Axelsson Raja, Joshua D. BackmanJohn Baksi, Paul J.R. Barton, Kiran J. Biddinger, Eric Boersma, Jeffrey Brandimarto, Søren Brunak, Henning Bundgaard, David J. Carey, Philippe Charron, James P. Cook, Stuart A. Cook, Spiros Denaxas, Jean François Deleuze, Alexander S. Doney, Perry Elliott, Christian Erikstrup, Tõnu Esko, Eric H. Farber-Eger, Chris Finan, Sophie Garnier, Jonas Ghouse, Vilmantas Giedraitis, Daniel F. Guðbjartsson, Vinicius Tragante, Jessica van Setten, Marion van Vugt, W. M.Monique Verschuren, Marion van Vugt, Folkert W. Asselbergs, , , ,

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.

Original language	English
Article number	2254
Pages (from-to)	2646–2658
Number of pages	13
Journal	Nature genetics
Volume	56
Issue number	12
Early online date	21 Nov 2024
DOIs	https://doi.org/10.1038/s41588-024-01952-y
Publication status	Published - 2024

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Zheng, S. L., Henry, A., Cannie, D., Lee, M., Miller, D., McGurk, K. A., Bond, I., Xu, X., Issa, H., Francis, C., De Marvao, A., Theotokis, P. I., Buchan, R. J., Speed, D., Abner, E., Adams, L., Aragam, K. G., Ärnlöv, J., Raja, A. A. (2024). Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy. Nature genetics, 56(12), 2646–2658 . Article 2254. https://doi.org/10.1038/s41588-024-01952-y

@article{b81e6c708dc247d9a0f6e273608a350a,

title = "Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy",

abstract = "Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.",

author = "Zheng, {Sean L.} and Albert Henry and Douglas Cannie and Michael Lee and David Miller and McGurk, {Kathryn A.} and Isabelle Bond and Xiao Xu and Hanane Issa and Catherine Francis and {De Marvao}, Antonio and Theotokis, {Pantazis I.} and Buchan, {Rachel J.} and Doug Speed and Erik Abner and Lance Adams and Aragam, {Krishna G.} and Johan {\"A}rnl{\"o}v and Raja, {Anna Axelsson} and Backman, {Joshua D.} and John Baksi and Barton, {Paul J.R.} and Biddinger, {Kiran J.} and Eric Boersma and Jeffrey Brandimarto and S{\o}ren Brunak and Henning Bundgaard and Carey, {David J.} and Philippe Charron and Cook, {James P.} and Cook, {Stuart A.} and Spiros Denaxas and Deleuze, {Jean Fran{\c c}ois} and Doney, {Alexander S.} and Perry Elliott and Christian Erikstrup and T{\~o}nu Esko and Farber-Eger, {Eric H.} and Chris Finan and Sophie Garnier and Jonas Ghouse and Vilmantas Giedraitis and Gu{\dh}bjartsson, {Daniel F.} and Vinicius Tragante and {van Setten}, Jessica and {van Vugt}, Marion and Verschuren, {W. M.Monique} and {van Vugt}, Marion and Asselbergs, {Folkert W.}",

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

year = "2024",

doi = "10.1038/s41588-024-01952-y",

language = "English",

volume = "56",

pages = "2646–2658 ",

journal = "Nature genetics",

issn = "1061-4036",

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Zheng, SL, Henry, A, Cannie, D, Lee, M, Miller, D, McGurk, KA, Bond, I, Xu, X, Issa, H, Francis, C, De Marvao, A, Theotokis, PI, Buchan, RJ, Speed, D, Abner, E, Adams, L, Aragam, KG, Ärnlöv, J, Raja, AA, Backman, JD, Baksi, J, Barton, PJR, Biddinger, KJ, Boersma, E, Brandimarto, J, Brunak, S, Bundgaard, H, Carey, DJ, Charron, P, Cook, JP, Cook, SA, Denaxas, S, Deleuze, JF, Doney, AS, Elliott, P, Erikstrup, C, Esko, T, Farber-Eger, EH, Finan, C, Garnier, S, Ghouse, J, Giedraitis, V, Guðbjartsson, DF, Tragante, V, van Setten, J , van Vugt, M , Verschuren, WMM , van Vugt, M , Asselbergs, FW 2024, 'Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy', Nature genetics, vol. 56, no. 12, 2254, pp. 2646–2658 . https://doi.org/10.1038/s41588-024-01952-y

TY - JOUR

T1 - Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

AU - Zheng, Sean L.

AU - Henry, Albert

AU - Cannie, Douglas

AU - Lee, Michael

AU - Miller, David

AU - McGurk, Kathryn A.

AU - Bond, Isabelle

AU - Xu, Xiao

AU - Issa, Hanane

AU - Francis, Catherine

AU - De Marvao, Antonio

AU - Theotokis, Pantazis I.

AU - Buchan, Rachel J.

AU - Speed, Doug

AU - Abner, Erik

AU - Adams, Lance

AU - Aragam, Krishna G.

AU - Ärnlöv, Johan

AU - Raja, Anna Axelsson

AU - Backman, Joshua D.

AU - Baksi, John

AU - Barton, Paul J.R.

AU - Biddinger, Kiran J.

AU - Boersma, Eric

AU - Brandimarto, Jeffrey

AU - Brunak, Søren

AU - Bundgaard, Henning

AU - Carey, David J.

AU - Charron, Philippe

AU - Cook, James P.

AU - Cook, Stuart A.

AU - Denaxas, Spiros

AU - Deleuze, Jean François

AU - Doney, Alexander S.

AU - Elliott, Perry

AU - Erikstrup, Christian

AU - Esko, Tõnu

AU - Farber-Eger, Eric H.

AU - Finan, Chris

AU - Garnier, Sophie

AU - Ghouse, Jonas

AU - Giedraitis, Vilmantas

AU - Guðbjartsson, Daniel F.

AU - Tragante, Vinicius

AU - van Setten, Jessica

AU - van Vugt, Marion

AU - Verschuren, W. M.Monique

AU - van Vugt, Marion

AU - Asselbergs, Folkert W.

PY - 2024

Y1 - 2024

N2 - Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.

AB - Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.

UR - http://www.scopus.com/inward/record.url?scp=85210019601&partnerID=8YFLogxK

U2 - 10.1038/s41588-024-01952-y

DO - 10.1038/s41588-024-01952-y

M3 - Article

AN - SCOPUS:85210019601

SN - 1061-4036

VL - 56

SP - 2646

EP - 2658

JO - Nature genetics

JF - Nature genetics

IS - 12

M1 - 2254

ER -

Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

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