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; Christopher M. Haggerty; Brian P. Halliday; Lars Lind; Sisse R. Ostrowski; Ole B.V. Pedersen; Henrik Ullum; Ole B.V. Pedersen; COVIDsortium; DBDS Genomic Consortium; Estonian Biobank Research Team; HERMES Consortium

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, Christopher M. Haggerty, Brian P. Halliday, Lars Lind, Sisse R. Ostrowski, Ole B.V. Pedersen, Henrik Ullum, Ole B.V. Pedersen, COVIDsortium, DBDS Genomic Consortium, Estonian Biobank Research Team, HERMES Consortium

Research output: Contribution to journal › Journal article › Research › peer-review

1 Citation (Scopus)

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
Journal	Nature Genetics
Number of pages	32
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-024-01952-y
Publication status	Accepted/In press - 2024

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Publisher Copyright:
© The Author(s) 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., ... HERMES Consortium (Accepted/In press). Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy. Nature Genetics. https://doi.org/10.1038/s41588-024-01952-y

Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy. / Zheng, Sean L.; Henry, Albert; Cannie, Douglas; Lee, Michael; Miller, David; McGurk, Kathryn A.; Bond, Isabelle; Xu, Xiao; Issa, Hanane; Francis, Catherine; De Marvao, Antonio; Theotokis, Pantazis I.; Buchan, Rachel J.; Speed, Doug; Abner, Erik; Adams, Lance; Aragam, Krishna G.; Ärnlöv, Johan; Raja, Anna Axelsson; Backman, Joshua D.; Baksi, John; Barton, Paul J.R.; Biddinger, Kiran J.; Boersma, Eric; Brandimarto, Jeffrey; Brunak, Søren ; Bundgaard, Henning; Carey, David J.; Charron, Philippe; Cook, James P.; Cook, Stuart A.; Denaxas, Spiros; Deleuze, Jean François; Doney, Alexander S.; Elliott, Perry; Erikstrup, Christian; Esko, Tõnu; Farber-Eger, Eric H.; Finan, Chris; Garnier, Sophie; Ghouse, Jonas; Giedraitis, Vilmantas; Guðbjartsson, Daniel F.; Haggerty, Christopher M.; Halliday, Brian P.; Lind, Lars; Ostrowski, Sisse R.; Pedersen, Ole B.V.; Ullum, Henrik; Pedersen, Ole B.V.; COVIDsortium; DBDS Genomic Consortium; Estonian Biobank Research Team; HERMES Consortium.

In: Nature Genetics, 2024.

Research output: Contribution to journal › Journal article › Research › peer-review

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, Haggerty, CM, Halliday, BP, Lind, L, Ostrowski, SR , Pedersen, OBV, Ullum, H, Pedersen, OBV, COVIDsortium, DBDS Genomic Consortium, Estonian Biobank Research Team & HERMES Consortium 2024, 'Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy', Nature Genetics. https://doi.org/10.1038/s41588-024-01952-y

Zheng, Sean L. ; Henry, Albert ; Cannie, Douglas ; Lee, Michael ; Miller, David ; McGurk, Kathryn A. ; Bond, Isabelle ; Xu, Xiao ; Issa, Hanane ; Francis, Catherine ; De Marvao, Antonio ; Theotokis, Pantazis I. ; Buchan, Rachel J. ; Speed, Doug ; Abner, Erik ; Adams, Lance ; Aragam, Krishna G. ; Ärnlöv, Johan ; Raja, Anna Axelsson ; Backman, Joshua D. ; Baksi, John ; Barton, Paul J.R. ; Biddinger, Kiran J. ; Boersma, Eric ; Brandimarto, Jeffrey ; Brunak, Søren ; Bundgaard, Henning ; Carey, David J. ; Charron, Philippe ; Cook, James P. ; Cook, Stuart A. ; Denaxas, Spiros ; Deleuze, Jean François ; Doney, Alexander S. ; Elliott, Perry ; Erikstrup, Christian ; Esko, Tõnu ; Farber-Eger, Eric H. ; Finan, Chris ; Garnier, Sophie ; Ghouse, Jonas ; Giedraitis, Vilmantas ; Guðbjartsson, Daniel F. ; Haggerty, Christopher M. ; Halliday, Brian P. ; Lind, Lars ; Ostrowski, Sisse R. ; Pedersen, Ole B.V. ; Ullum, Henrik ; Pedersen, Ole B.V. ; COVIDsortium ; DBDS Genomic Consortium ; Estonian Biobank Research Team ; HERMES Consortium. / Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy. In: Nature Genetics. 2024.

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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 Haggerty, {Christopher M.} and Halliday, {Brian P.} and Lars Lind and Ostrowski, {Sisse R.} and Pedersen, {Ole B.V.} and Henrik Ullum and Pedersen, {Ole B.V.} and COVIDsortium and {DBDS Genomic Consortium} and {Estonian Biobank Research Team} and {HERMES Consortium}",

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year = "2024",

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

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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 - Haggerty, Christopher M.

AU - Halliday, Brian P.

AU - Lind, Lars

AU - Ostrowski, Sisse R.

AU - Pedersen, Ole B.V.

AU - Ullum, Henrik

AU - Pedersen, Ole B.V.

AU - COVIDsortium

AU - DBDS Genomic Consortium

AU - Estonian Biobank Research Team

AU - HERMES Consortium

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.

U2 - 10.1038/s41588-024-01952-y

DO - 10.1038/s41588-024-01952-y

M3 - Journal article

C2 - 39572783

AN - SCOPUS:85210019601

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -