PRESENTATION ABSTRACTS
#20 Dual-species multi-omics approach suggests novel candidate genes for dilated cardiomyopathy in dog and human * co-senior authors # corresponding author Niskanen JE 1,2,3 , Ohlsson Å 4 , Ljungvall I 5 , Drögemüller M 6 , Harakalova M 7,8 , Ernst RF 9 , Dooijes D 9 , van Tintelen PJ 9 , Snijders Blok CJB 8 , van Vugt M 8 , van Setten J 8 , Asselbergs FW 8 , Domanjko Petri č A 10 , Salonen M 1,2,3 , Hörtenhuber M 11 , DoGA consortium, Pyle WG 12,13 , Donner J 14 , Postma AV 15,16 , Leeb T 6 , Andersson G 4 , Hytönen MK 1,2,3 , Häggström J 5 , Wiberg M 17 , Friederich J 18 , Eberhard J 18 , van Steenbeek FG 7,8,19 *, Wess G 17 *, Lohi H 1,2,3 *# julia.niskanen@helsinki.fi 1 Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland, 2 Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland, 3 Folkhälsan Research Center, Helsinki, Finland, 4 Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden, 5 Department of Clinical Sciences, Swedish University of Agricultural Sciences, Up- psala, Sweden, 6 Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland, 7 Department of Cardiology, University Medical Center Utrecht (UMCU) and Regenerative Medicine Utrecht (RMU), Utrecht, The Netherlands, 8 Department of Cardiology, Division Heart & Lungs, UMC Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands, 9 Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands, 10 Small Animal Clinic, Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia, 11 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden, 12 Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada, 13 IMPART Investigator Team Canada, Dalhousie Medicine, Saint John, New Brunswick, Canada, 14 Wisdom Panel Research Team, Wisdom Panel, Kinship, Helsinki, Finland, 15 De- partment of Human Genetics, Amsterdam University Medical Center, The Netherlands, 16 Department of Medical Biology, Amsterdam University Medical Center, The Netherlands, 17 Department of Equine and Small Animal Medicine, University of Helsinki, Finland, 18 Clinic of Small Animal Medicine, Ludwig-Max- imilians-Universität München, München, Germany, 19 Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands 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. We performed GWAS followed by whole-genome, transcriptome and immunohistochemical analyses in a canine model of DCM. Our results revealed two statistically significant independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes involved in cardiac action potentials, energy homeostasis and morphology. We further illustrate the distinct genetic etiology underlying the typical DCM phenotype but not ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes. Collectively, our study yields insight into the molecular pathophysiology of DCM and provided a large animal model for preclinical studies.
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