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

• Published in: Genome medicine 2023-09, Vol.15 (1), p.1-73, Article 73
• Main Authors: Niskanen, Julia E, Ohlsson, Ãsa, Ljungvall, Ingrid, Drögemüller, Michaela, Ernst, Robert F, Dooijes, Dennis, van Deutekom, Hanneke W. M, van Tintelen, J. Peter, Snijders Blok, Christian J. B, van Vugt, Marion, van Setten, Jessica, Asselbergs, Folkert W, Petric, Aleksandra Domanjko, Salonen, Milla, Hundi, Sruthi, Hörtenhuber, Matthias, Daub, Carsten, Araujo, César L, Quintero, Ileana B, Kyöstilä, Kaisa, Kaukonen, Maria, Arumilli, Meharji, Sarviaho, Riika, Puurunen, Jenni, Sulkama, Sini, Karjalainen, Sini, Sukura, Antti, Syrjä, Pernilla, Airas, Niina, Pekkarinen, Henna, Kareinen, Ilona, Javela, Hanna-Maaria, Knuuttila, Anna, Nordgren, Heli, Hagner, Karoliina, Pääkkönen, Tarja, Iivanainen, Antti, Krjutskov, Kaarel, Ezer, Sini, Saarinen, Auli, Katayama, Shintaro, Yoshihara, Masahito, Mukarram, Abdul Kadir, Aljelaify, Rasha Fahad, Ross, Fiona, Raman, Amitha, Stevens, Irene, Gusev, Oleg, Bannasch, Danika, Schoenebeck, Jeffrey J
• Format: Article
• Language: English
• Subjects: Animal models; Arrhythmia; Biotechnology industry; Cardiac; Cardiac arrhythmia; Cardiology; Cardiomyopathy; Clinics; Companion animal; Congestive heart failure; Development and progression; Dilated cardiomyopathy; Disease; Dogs; Energy balance; Ethics; Ethylenediaminetetraacetic acid; Genetic research; Genetic testing; Genetics; Genetik; Genomes; Genomics; GWAS; Health risk assessment; Heart; Heart diseases; Homeostasis; Medicin och hälsovetenskap; Pathobiology; Patobiologi; Phenotypes; Risk factors; Transcriptomes; Ventricle
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-023-01221-3

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: Cardiac, Cardiology, Genetics, Companion animal, Arrhythmia, GWAS, Complex trait, Transcriptomics