Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy


  • M. Heinig
  • M.E. Adriaens
  • S. Schafer
  • H.W.M. van Deutekom
  • E.M. Lodder
  • J.S. Ware
  • V. Schneider
  • L.E. Felkin
  • E.E. Creemers
  • B. Meder
  • H.A. Katus
  • F. Rühle
  • M. Stoll
  • F. Cambien
  • E. Villard
  • P. Charron
  • A. Varro
  • N.H. Bishopric
  • A.L. George
  • C. Dos Remedios
  • A. Moreno-Moral
  • F. Pesce
  • A. Bauerfeind
  • F. Rüschendorf
  • C. Rintisch
  • E. Petretto
  • P.J. Barton
  • S.A. Cook
  • Y.M. Pinto
  • C.R. Bezzina
  • N. Hubner


  • Genome Biology


  • Genome Biol 18 (1): 170


  • 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.