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 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

16 Citations (Scopus)

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

Fingerprint

cardiomyopathy
Dilated Cardiomyopathy
Transcriptome
transcriptome
genetic variation
phenotype
RNA
genome
Tissue Donors
allele
RNA Splicing
transcription (genetics)
gene
heart
cardiovascular disease
Genome
Phenotype
gene expression
Alleles
RNA Sequence Analysis

Keywords

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

ASJC Scopus subject areas

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

Cite this

Heinig, M., Adriaens, M. E., Schafer, S., van Deutekom, H. W. M., Lodder, E. M., Ware, J. S., ... 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

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy. / Heinig, Matthias; Adriaens, Michiel E.; Schafer, Sebastian; van Deutekom, Hanneke W.M.; Lodder, Elisabeth M.; Ware, James S.; Schneider, Valentin; Felkin, Leanne E.; Creemers, Esther E.; Meder, Benjamin; Katus, Hugo A.; Rühle, Frank; Stoll, Monika; Cambien, François; Villard, Eric; Charron, Philippe; Varro, Andras; Bishopric, Nanette; George, Alfred L.; dos Remedios, Cristobal; Moreno-Moral, Aida; Pesce, Francesco; Bauerfeind, Anja; Rüschendorf, Franz; Rintisch, Carola; Petretto, Enrico; Barton, Paul J.; Cook, Stuart A.; Pinto, Yigal M.; Bezzina, Connie R.; Hubner, Norbert.

In: Genome Biology, Vol. 18, No. 1, 170, 14.09.2017.

Research output: Contribution to journalArticle

Heinig, M, Adriaens, ME, Schafer, S, van Deutekom, HWM, Lodder, EM, Ware, JS, Schneider, V, Felkin, LE, Creemers, EE, Meder, B, Katus, HA, Rühle, F, Stoll, M, Cambien, F, Villard, E, Charron, P, Varro, A, Bishopric, N, George, AL, dos Remedios, C, Moreno-Moral, A, Pesce, F, Bauerfeind, A, Rüschendorf, F, Rintisch, C, Petretto, E, Barton, PJ, Cook, SA, Pinto, YM, Bezzina, CR & Hubner, N 2017, 'Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy', Genome Biology, vol. 18, no. 1, 170. https://doi.org/10.1186/s13059-017-1286-z
Heinig, Matthias ; Adriaens, Michiel E. ; Schafer, Sebastian ; van Deutekom, Hanneke W.M. ; Lodder, Elisabeth M. ; Ware, James S. ; Schneider, Valentin ; Felkin, Leanne E. ; Creemers, Esther E. ; Meder, Benjamin ; Katus, Hugo A. ; Rühle, Frank ; Stoll, Monika ; Cambien, François ; Villard, Eric ; Charron, Philippe ; Varro, Andras ; Bishopric, Nanette ; George, Alfred L. ; dos Remedios, Cristobal ; Moreno-Moral, Aida ; Pesce, Francesco ; Bauerfeind, Anja ; Rüschendorf, Franz ; Rintisch, Carola ; Petretto, Enrico ; Barton, Paul J. ; Cook, Stuart A. ; Pinto, Yigal M. ; Bezzina, Connie R. ; Hubner, Norbert. / Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy. In: Genome Biology. 2017 ; Vol. 18, No. 1.
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AU - van Deutekom, Hanneke W.M.

AU - Lodder, Elisabeth M.

AU - Ware, James S.

AU - Schneider, Valentin

AU - Felkin, Leanne E.

AU - Creemers, Esther E.

AU - Meder, Benjamin

AU - Katus, Hugo A.

AU - Rühle, Frank

AU - Stoll, Monika

AU - Cambien, François

AU - Villard, Eric

AU - Charron, Philippe

AU - Varro, Andras

AU - Bishopric, Nanette

AU - George, Alfred L.

AU - dos Remedios, Cristobal

AU - Moreno-Moral, Aida

AU - Pesce, Francesco

AU - Bauerfeind, Anja

AU - Rüschendorf, Franz

AU - Rintisch, Carola

AU - Petretto, Enrico

AU - Barton, Paul J.

AU - Cook, Stuart A.

AU - Pinto, Yigal M.

AU - Bezzina, Connie R.

AU - Hubner, Norbert

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N2 - 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.

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