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

COVIDsortium; 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; Anna Helgadottir; Harry Hemingway; Hans L Hillege; Isabella Kardys; Lars Lind; Ole Birger Vesterager Pedersen

doi:10.1038/s41588-024-01952-y

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

COVIDsortium, 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 RajaJoshua 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, Anna Helgadottir, Harry Hemingway, Hans L Hillege, Isabella Kardys, Lars Lind, Ole Birger Vesterager Pedersen

Klinisk Immunologisk Afdeling

Publikation: Bidrag til tidsskrift › Artikel › Forskning › 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.

Originalsprog	Engelsk
Sider (fra-til)	2646-2658
Antal sider	13
Tidsskrift	Nature Genetics
Vol/bind	56
Udgave nummer	12
DOI	https://doi.org/10.1038/s41588-024-01952-y
Status	Udgivet - dec. 2024

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10.1038/s41588-024-01952-y

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COVIDsortium, 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., ... Pedersen, O. B. V. (2024). Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy. Nature Genetics, 56(12), 2646-2658. https://doi.org/10.1038/s41588-024-01952-y

@article{8538e79e61cb4faa809924c0800e784b,

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.",

keywords = "Cardiomyopathy, Dilated/genetics, Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Nedd4 Ubiquitin Protein Ligases/genetics, Polymorphism, Single Nucleotide, Multifactorial Inheritance/genetics, Male, Female, Quantitative Trait Loci",

author = "COVIDsortium and 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 Jean-Fran{\c c}ois Deleuze 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 Anna Helgadottir and Harry Hemingway and Hillege, {Hans L} and Isabella Kardys and Lars Lind and Pedersen, {Ole Birger Vesterager}",

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

year = "2024",

month = dec,

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

language = "English",

volume = "56",

pages = "2646--2658",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

COVIDsortium, 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, J-F, 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, Helgadottir, A, Hemingway, H, Hillege, HL, Kardys, I, Lind, L & Pedersen, OBV 2024, 'Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy', Nature Genetics, bind 56, nr. 12, s. 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 - COVIDsortium

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 - Helgadottir, Anna

AU - Hemingway, Harry

AU - Hillege, Hans L

AU - Kardys, Isabella

AU - Lind, Lars

AU - Pedersen, Ole Birger Vesterager

PY - 2024/12

Y1 - 2024/12

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.

KW - Cardiomyopathy, Dilated/genetics

KW - Humans

KW - Genome-Wide Association Study

KW - Genetic Predisposition to Disease

KW - Nedd4 Ubiquitin Protein Ligases/genetics

KW - Polymorphism, Single Nucleotide

KW - Multifactorial Inheritance/genetics

KW - Male

KW - Female

KW - Quantitative Trait Loci

U2 - 10.1038/s41588-024-01952-y

DO - 10.1038/s41588-024-01952-y

M3 - Article

C2 - 39572783

SN - 1061-4036

VL - 56

SP - 2646

EP - 2658

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

Abstract

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