Genetic and functional insights into the fractal structure of the heart

Hannah V. Meyer; Timothy J.W. Dawes; Marta Serrani; Wenjia Bai; Paweł Tokarczuk; Jiashen Cai; Antonio de Marvao; Albert Henry; R. Thomas Lumbers; Jakob Gierten; Thomas Thumberger; Joachim Wittbrodt; James S. Ware; Daniel Rueckert; Paul M. Matthews; Sanjay K. Prasad; Maria L. Costantino; Stuart A. Cook; Ewan Birney; Declan P. O’Regan

doi:10.1038/s41586-020-2635-8

Genetic and functional insights into the fractal structure of the heart

Hannah V. Meyer, Timothy J.W. Dawes, Marta Serrani, Wenjia Bai, Paweł Tokarczuk, Jiashen Cai, Antonio de Marvao, Albert Henry, R. Thomas Lumbers, Jakob Gierten, Thomas Thumberger, Joachim Wittbrodt, James S. Ware, Daniel Rueckert, Paul M. Matthews, Sanjay K. Prasad, Maria L. Costantino, Stuart A. Cook, Ewan Birney, Declan P. O’Regan

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

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Abstract

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development^1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization^3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.

Original language	English
Pages (from-to)	589-594
Number of pages	6
Journal	Nature
Volume	584
Issue number	7822
DOIs	https://doi.org/10.1038/s41586-020-2635-8
State	Published - 27 Aug 2020
Externally published	Yes

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Meyer, H. V., Dawes, T. J. W., Serrani, M., Bai, W., Tokarczuk, P., Cai, J., de Marvao, A., Henry, A., Lumbers, R. T., Gierten, J., Thumberger, T., Wittbrodt, J., Ware, J. S., Rueckert, D., Matthews, P. M., Prasad, S. K., Costantino, M. L., Cook, S. A., Birney, E., & O’Regan, D. P. (2020). Genetic and functional insights into the fractal structure of the heart. Nature, 584(7822), 589-594. https://doi.org/10.1038/s41586-020-2635-8

@article{e76222867ece4ffb8c5a006426175754,

title = "Genetic and functional insights into the fractal structure of the heart",

abstract = "The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.",

author = "Meyer, {Hannah V.} and Dawes, {Timothy J.W.} and Marta Serrani and Wenjia Bai and Pawe{\l} Tokarczuk and Jiashen Cai and {de Marvao}, Antonio and Albert Henry and Lumbers, {R. Thomas} and Jakob Gierten and Thomas Thumberger and Joachim Wittbrodt and Ware, {James S.} and Daniel Rueckert and Matthews, {Paul M.} and Prasad, {Sanjay K.} and Costantino, {Maria L.} and Cook, {Stuart A.} and Ewan Birney and O{\textquoteright}Regan, {Declan P.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = aug,

day = "27",

doi = "10.1038/s41586-020-2635-8",

language = "English",

volume = "584",

pages = "589--594",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

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Meyer, HV, Dawes, TJW, Serrani, M, Bai, W, Tokarczuk, P, Cai, J, de Marvao, A, Henry, A, Lumbers, RT, Gierten, J, Thumberger, T, Wittbrodt, J, Ware, JS, Rueckert, D, Matthews, PM, Prasad, SK, Costantino, ML, Cook, SA, Birney, E & O’Regan, DP 2020, 'Genetic and functional insights into the fractal structure of the heart', Nature, vol. 584, no. 7822, pp. 589-594. https://doi.org/10.1038/s41586-020-2635-8

TY - JOUR

T1 - Genetic and functional insights into the fractal structure of the heart

AU - Meyer, Hannah V.

AU - Dawes, Timothy J.W.

AU - Serrani, Marta

AU - Bai, Wenjia

AU - Tokarczuk, Paweł

AU - Cai, Jiashen

AU - de Marvao, Antonio

AU - Henry, Albert

AU - Lumbers, R. Thomas

AU - Gierten, Jakob

AU - Thumberger, Thomas

AU - Wittbrodt, Joachim

AU - Ware, James S.

AU - Rueckert, Daniel

AU - Matthews, Paul M.

AU - Prasad, Sanjay K.

AU - Costantino, Maria L.

AU - Cook, Stuart A.

AU - Birney, Ewan

AU - O’Regan, Declan P.

PY - 2020/8/27

Y1 - 2020/8/27

N2 - The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.

AB - The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.

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DO - 10.1038/s41586-020-2635-8

M3 - Article

C2 - 32814899

AN - SCOPUS:85089602988

SN - 0028-0836

VL - 584

SP - 589

EP - 594

JO - Nature

JF - Nature

IS - 7822

ER -

Genetic and functional insights into the fractal structure of the heart

Abstract

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