Genome Biology (Sep 2017)
Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy
- Matthias Heinig,
- Michiel E. Adriaens,
- Sebastian Schafer,
- Hanneke W. M. van Deutekom,
- Elisabeth M. Lodder,
- James S. Ware,
- Valentin Schneider,
- Leanne E. Felkin,
- Esther E. Creemers,
- Benjamin Meder,
- Hugo A. Katus,
- Frank Rühle,
- Monika Stoll,
- François Cambien,
- Eric Villard,
- Philippe Charron,
- Andras Varro,
- Nanette H. Bishopric,
- Alfred L. George,
- Cristobal dos Remedios,
- Aida Moreno-Moral,
- Francesco Pesce,
- Anja Bauerfeind,
- Franz Rüschendorf,
- Carola Rintisch,
- Enrico Petretto,
- Paul J. Barton,
- Stuart A. Cook,
- Yigal M. Pinto,
- Connie R. Bezzina,
- Norbert Hubner
Affiliations
- Matthias Heinig
- Institute of Computational Biology, Helmholtz Zentrum München
- Michiel E. Adriaens
- Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam
- Sebastian Schafer
- National Heart Research Institute Singapore, National Heart Centre Singapore
- Hanneke W. M. van Deutekom
- Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam
- Elisabeth M. Lodder
- Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam
- James S. Ware
- National Heart and Lung Institute, Imperial College London
- Valentin Schneider
- Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
- Leanne E. Felkin
- National Heart and Lung Institute, Imperial College London
- Esther E. Creemers
- Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam
- Benjamin Meder
- Institute for Cardiomyopathies Heidelberg & Department of Cardiology, Angiology and Pneumology, University Heidelberg
- Hugo A. Katus
- Institute for Cardiomyopathies Heidelberg & Department of Cardiology, Angiology and Pneumology, University Heidelberg
- Frank Rühle
- Institute of Human Genetics, Genetic Epidemiology, University of Münster
- Monika Stoll
- Institute of Human Genetics, Genetic Epidemiology, University of Münster
- François Cambien
- Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases
- Eric Villard
- Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases
- Philippe Charron
- ICAN Institute for Cardiometabolism and Nutrition
- Andras Varro
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged
- Nanette H. Bishopric
- Department of Medicine, University of Miami School of Medicine
- Alfred L. George
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University
- Cristobal dos Remedios
- Sydney Heart Bank, Department of Anatomy, Bosch Institute, The University of Sydney
- Aida Moreno-Moral
- Program in Cardiovascular and Metabolic Disorders, Center for Computational Biology, DUKE-NUS Medical School
- Francesco Pesce
- National Heart and Lung Institute, Imperial College London
- Anja Bauerfeind
- Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
- Franz Rüschendorf
- Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
- Carola Rintisch
- Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
- Enrico Petretto
- Program in Cardiovascular and Metabolic Disorders, Center for Computational Biology, DUKE-NUS Medical School
- Paul J. Barton
- National Heart and Lung Institute, Imperial College London
- Stuart A. Cook
- National Heart Research Institute Singapore, National Heart Centre Singapore
- Yigal M. Pinto
- Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam
- Connie R. Bezzina
- Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam
- Norbert Hubner
- Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
- DOI
- https://doi.org/10.1186/s13059-017-1286-z
- Journal volume & issue
-
Vol. 18,
no. 1
pp. 1 – 21
Abstract
Abstract Background Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases. Results Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts. Conclusions RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics.
Keywords
