Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human

Julia E Niskanen; Åsa Ohlsson; Ingrid Ljungvall; Michaela Drögemüller; Robert F Ernst; Dennis Dooijes; Hanneke W M van Deutekom; J Peter van Tintelen; Christian J B Snijders Blok; Marion van Vugt; Jessica van Setten; Folkert W Asselbergs; Aleksandra Domanjko Petrič; Milla Salonen; Sruthi Hundi; Matthias Hörtenhuber; Juha Kere; W Glen Pyle; Jonas Donner; Alex V Postma; Tosso Leeb; Göran Andersson; Marjo K Hytönen; Jens Häggström; Maria Wiberg; Jana Friederich; Jenny Eberhard; Magdalena Harakalova; Frank G van Steenbeek; Gerhard Wess; Hannes Lohi

doi:10.1186/s13073-023-01221-3

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human

Julia E Niskanen, Åsa Ohlsson, Ingrid Ljungvall, Michaela Drögemüller, Robert F Ernst, Dennis Dooijes, Hanneke W M van Deutekom, J Peter van Tintelen, Christian J B Snijders Blok, Marion van Vugt, Jessica van Setten, Folkert W Asselbergs, Aleksandra Domanjko Petrič, Milla Salonen, Sruthi Hundi, Matthias Hörtenhuber, Juha Kere, W Glen Pyle, Jonas Donner, Alex V PostmaTosso Leeb, Göran Andersson, Marjo K Hytönen, Jens Häggström, Maria Wiberg, Jana Friederich, Jenny Eberhard, Magdalena Harakalova, Frank G van Steenbeek, Gerhard Wess, Hannes Lohi

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

Abstract

BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.

METHODS: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts.

RESULTS: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes.

CONCLUSIONS: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.

Original language	English
Article number	73
Number of pages	21
Journal	Genome Medicine
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s13073-023-01221-3
Publication status	Published - 18 Sept 2023

Bibliographical note

Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.

Funding

Open Access funding provided by University of Helsinki including Helsinki University Central Hospital. This study was partially supported by the Canine Health Foundation (Grant #2631), the Wisdom Health, the Jane and Aatos Erkko Foundation, the University of Helsinki Doctoral Programme in Integrative Life Science, the Finnish Foundation for Cardiovascular Research, the Academy of Finland, HiLIFE, the OVC Pet Trust, Sigrid Juselius Foundation, the Swedish Research Council, and The Research Council for Environment, Agricultural Sciences, European Research Area Network on Cardiovascular Diseases ERA-CVD grant (SCALE no. 2019T109), Leducq grant (CURE-PLaN no. 18CVD01, ZonMW Open Competition grant CONTRACT no. 09120012010018, and Spatial Planning (Formas) (Project: 2017-00559). Folkert Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Support from the Dutch Cardiovascular Alliance (DCVA) study Double-Dose (2020B005) and the Netherlands Cardiovascular Research Initiative (CVON), an initiative supported by the Dutch Heart Foundation (PREDICT2 2018-30, eDETECT 2015-12), is acknowledged. The samples were collected under the permission of the animal ethical committee of the County Administrative Board of Southern Finland (ESAVI/6054/04.10.03/2012, ESAVI/343/04.10.07/2016, and ESAVI/25696/2020); the ethical committee of the Center of Clinical Medicine, Munich, LMU University (60-18-11-2015); and the ethical committee of the Swedish Board of Agriculture (No. C2/12 (2012-02-24) and No. C12/15 (2015-02-27)). All sampling procedures in clinics conformed to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals. The human data collection was in accordance with the principles of the Declaration of Helsinki, and written informed consent was obtained from the subjects of whom data were presented according to the UNRAVEL protocol (Medical Ethical Committee (TCBio) of University Medical Center (UMC) Utrecht; approval number: 12–387 (UNRAVEL)). Sini Karjalainen, Kaisu Hiltunen, Ileana Quintero, Reetta Hänninen, Heli Venhoranta, and Nina Puolatie are acknowledged for the technical assistance; Meharji Arumilli for the bioinformatic processing; and Lynne O’Sullivan for the veterinary expertise. We thank the Dog Biomedical Variant Database Consortium (Gus Aguirre, Catherine André, Danika Bannasch, Doreen Becker, Cord Drögemüller, Kari Ekenstedt, Kiterie Faller, Oliver Forman, Steve Friedenberg, Eva Furrow, Urs Giger, Christophe Hitte, Marjo Hytönen, Hannes Lohi, Cathryn Mellersh, Jim Mickelson, Leonardo Murgiano, Anita Oberbauer, Sheila Schmutz, Jeffrey Schoenebeck, Kim Summers, Frank van Steenbeek, and Claire Wade) for sharing the genome sequence data from dogs and wolves and the DoGA consortium (Hannes Lohi, Juha Kere, Carsten Daub, Marjo K. Hytönen, César L. Araujo, Ileana B. Quintero, Kaisa Kyöstilä, Maria Kaukonen, Meharji Arumilli, Milla Salonen, Riika Sarviaho, Julia Niskanen, Sruthi Hundi, Jenni Puurunen, Sini Sulkama, Sini Karjalainen, Antti Sukura, Pernilla Syrjä, Niina Airas, Henna Pekkarinen, Ilona Kareinen, Hanna-Maaria Javela, Anna Knuuttila, Heli Nordgren, Karoliina Hagner, Tarja Pääkkönen, Antti Iivanainen, Kaarel Krjutskov, Sini Ezer, Auli Saarinen, Shintaro Katayama, Masahito Yoshihara, Auli Saarinen, Abdul Kadir Mukarram, Matthias Hörtenhuber, Rasha Fahad Aljelaify, Fiona Ross, Amitha Raman, Irene Stevens, Oleg Gusev, Danika Bannasch, and Jeffrey J. Schoenebeck) for providing CAGE-seq data. We thank CSC - IT Center for Science Ltd. for the resources in data management and analysis. We also thank all the dog owners who have participated in the clinical examinations and donated samples from their dogs. This research has been conducted using the UK Biobank Resource under Application Number 24711.

Funders	Funder number
CVON
Center of Clinical Medicine
County Administrative Board of Southern Finland	ESAVI/6054/04.10.03/2012, ESAVI/25696/2020, ESAVI/343/04.10.07/2016
LMU University	60-18-11-2015
Netherlands Cardiovascular Research Initiative
Research Council for Environment, Agricultural Sciences	2019T109, 18CVD01
Spatial Planning (Formas)	2017-00559
Swedish Board of Agriculture	C12/15, 2015-02-27, C2/12, 2012-02-24
UCL Hospitals NIHR Biomedical Research Centre
ZonMW Open Competition	09120012010018
American Kennel Club Canine Health Foundation	2631
Helsingin Yliopisto
OVC Pet Trust
Dutch Cardiovascular Alliance	2020B005
Commonwealth Scholarship Commission
Academy of Finland
Hartstichting	PREDICT2 2018-30, eDETECT 2015-12
Jane ja Aatos Erkon Säätiö
Vetenskapsrådet
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö
CSC – IT Center for Science	24711

Keywords

Arrhythmia
Cardiac
Cardiology
Companion animal
Complex trait
GWAS
Genetics
Transcriptomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Niskanen, J. E., Ohlsson, Å., Ljungvall, I., Drögemüller, M., Ernst, R. F., Dooijes, D., van Deutekom, H. W. M., van Tintelen, J. P., Snijders Blok, C. J. B., van Vugt, M., van Setten, J., Asselbergs, F. W., Petrič, A. D., Salonen, M., Hundi, S., Hörtenhuber, M., Kere, J., Pyle, W. G., Donner, J., ... Lohi, H. (2023). Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human. Genome Medicine, 15(1), Article 73. https://doi.org/10.1186/s13073-023-01221-3

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title = "Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human",

abstract = "BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.METHODS: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts.RESULTS: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes.CONCLUSIONS: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.",

keywords = "Arrhythmia, Cardiac, Cardiology, Companion animal, Complex trait, GWAS, Genetics, Transcriptomics",

author = "Niskanen, {Julia E} and {\AA}sa Ohlsson and Ingrid Ljungvall and Michaela Dr{\"o}gem{\"u}ller and Ernst, {Robert F} and Dennis Dooijes and {van Deutekom}, {Hanneke W M} and {van Tintelen}, {J Peter} and {Snijders Blok}, {Christian J B} and {van Vugt}, Marion and {van Setten}, Jessica and Asselbergs, {Folkert W} and Petri{\v c}, {Aleksandra Domanjko} and Milla Salonen and Sruthi Hundi and Matthias H{\"o}rtenhuber and Juha Kere and Pyle, {W Glen} and Jonas Donner and Postma, {Alex V} and Tosso Leeb and G{\"o}ran Andersson and Hyt{\"o}nen, {Marjo K} and Jens H{\"a}ggstr{\"o}m and Maria Wiberg and Jana Friederich and Jenny Eberhard and Magdalena Harakalova and {van Steenbeek}, {Frank G} and Gerhard Wess and Hannes Lohi",

note = "Publisher Copyright: {\textcopyright} 2023, BioMed Central Ltd., part of Springer Nature.",

year = "2023",

month = sep,

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doi = "10.1186/s13073-023-01221-3",

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Niskanen, JE, Ohlsson, Å, Ljungvall, I, Drögemüller, M, Ernst, RF, Dooijes, D, van Deutekom, HWM, van Tintelen, JP, Snijders Blok, CJB, van Vugt, M, van Setten, J, Asselbergs, FW, Petrič, AD, Salonen, M, Hundi, S, Hörtenhuber, M, Kere, J, Pyle, WG, Donner, J, Postma, AV, Leeb, T, Andersson, G, Hytönen, MK, Häggström, J, Wiberg, M, Friederich, J, Eberhard, J, Harakalova, M, van Steenbeek, FG, Wess, G & Lohi, H 2023, 'Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human', Genome Medicine, vol. 15, no. 1, 73. https://doi.org/10.1186/s13073-023-01221-3

TY - JOUR

T1 - Identification of novel genetic risk factors of dilated cardiomyopathy

T2 - from canine to human

AU - Niskanen, Julia E

AU - Ohlsson, Åsa

AU - Ljungvall, Ingrid

AU - Drögemüller, Michaela

AU - Ernst, Robert F

AU - Dooijes, Dennis

AU - van Deutekom, Hanneke W M

AU - van Tintelen, J Peter

AU - Snijders Blok, Christian J B

AU - van Vugt, Marion

AU - van Setten, Jessica

AU - Asselbergs, Folkert W

AU - Petrič, Aleksandra Domanjko

AU - Salonen, Milla

AU - Hundi, Sruthi

AU - Hörtenhuber, Matthias

AU - Kere, Juha

AU - Pyle, W Glen

AU - Donner, Jonas

AU - Postma, Alex V

AU - Leeb, Tosso

AU - Andersson, Göran

AU - Hytönen, Marjo K

AU - Häggström, Jens

AU - Wiberg, Maria

AU - Friederich, Jana

AU - Eberhard, Jenny

AU - Harakalova, Magdalena

AU - van Steenbeek, Frank G

AU - Wess, Gerhard

AU - Lohi, Hannes

PY - 2023/9/18

Y1 - 2023/9/18

N2 - BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.METHODS: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts.RESULTS: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes.CONCLUSIONS: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.

AB - BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.METHODS: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts.RESULTS: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes.CONCLUSIONS: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.

KW - Arrhythmia

KW - Cardiac

KW - Cardiology

KW - Companion animal

KW - Complex trait

KW - GWAS

KW - Genetics

KW - Transcriptomics

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U2 - 10.1186/s13073-023-01221-3

DO - 10.1186/s13073-023-01221-3

M3 - Article

C2 - 37723491

SN - 1756-994X

VL - 15

JO - Genome Medicine

JF - Genome Medicine

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ER -

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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