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 RemediosAida 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

Research output: Contribution to journalArticle

25 Scopus citations

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.

Original languageEnglish (US)
Article number170
JournalGenome biology
Volume18
Issue number1
DOIs
StatePublished - Sep 14 2017

Keywords

  • Dilated cardiomyopathy
  • EQTL
  • Gene expression
  • Genetics
  • Heart

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

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    Heinig, M., Adriaens, M. E., Schafer, S., van Deutekom, H. W. M., Lodder, E. M., Ware, J. S., Schneider, V., Felkin, L. E., Creemers, E. E., Meder, B., Katus, H. A., Rühle, F., Stoll, M., Cambien, F., Villard, E., Charron, P., Varro, A., Bishopric, N. H., George, A. L., ... Hubner, N. (2017). Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy. Genome biology, 18(1), [170]. https://doi.org/10.1186/s13059-017-1286-z