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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

39 Citations (Web of Science)

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
Article number170
Pages (from-to)170
Number of pages21
JournalGenome Biology
Volume18
Issue number1
DOIs
Publication statusPublished - 14 Sep 2017

Keywords

  • Genetics
  • Gene expression
  • eQTL
  • Dilated cardiomyopathy
  • Heart
  • GENOME-WIDE ASSOCIATION
  • MITOCHONDRIAL THIOREDOXIN REDUCTASE
  • MYOCARDIAL ISCHEMIC-INJURY
  • LIGHT-CHAIN KINASE
  • MYOSIN HEAVY-CHAIN
  • FOLLISTATIN-LIKE 1
  • HEART-FAILURE
  • NATRIURETIC-PEPTIDES
  • EXPRESSION VARIATION
  • ATRIAL-FIBRILLATION

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