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

doi:10.1186/s13059-017-1286-z

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 journal › Article › Academic › peer-review

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 language	English
Article number	170
Number of pages	21
Journal	Genome Biology
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s13059-017-1286-z
Publication status	Published - 14 Sept 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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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), Article 170. https://doi.org/10.1186/s13059-017-1286-z

@article{808d3c70c39d40edbeae574c9cd09283,

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

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 = "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",

author = "Matthias Heinig and Adriaens, {Michiel E} and Sebastian Schafer and {van Deutekom}, {Hanneke W M} and Lodder, {Elisabeth M} and Ware, {James S} and Valentin Schneider and Felkin, {Leanne E} and Creemers, {Esther E} and Benjamin Meder and Katus, {Hugo A} and Frank R{\"u}hle and Monika Stoll and Fran{\c c}ois Cambien and Eric Villard and Philippe Charron and Andras Varro and Bishopric, {Nanette H} and George, {Alfred L} and {Dos Remedios}, Cristobal and Aida Moreno-Moral and Francesco Pesce and Anja Bauerfeind and Franz R{\"u}schendorf and Carola Rintisch and Enrico Petretto and Barton, {Paul J} and Cook, {Stuart A} and Pinto, {Yigal M} and Bezzina, {Connie R} and Norbert Hubner",

year = "2017",

month = sep,

day = "14",

doi = "10.1186/s13059-017-1286-z",

language = "English",

volume = "18",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central Ltd",

number = "1",

}

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, NH, 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

TY - JOUR

T1 - Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

AU - Heinig, Matthias

AU - Adriaens, Michiel E

AU - Schafer, Sebastian

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 H

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

PY - 2017/9/14

Y1 - 2017/9/14

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.

AB - 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.

KW - Genetics

KW - Gene expression

KW - eQTL

KW - Dilated cardiomyopathy

KW - Heart

KW - GENOME-WIDE ASSOCIATION

KW - MITOCHONDRIAL THIOREDOXIN REDUCTASE

KW - MYOCARDIAL ISCHEMIC-INJURY

KW - LIGHT-CHAIN KINASE

KW - MYOSIN HEAVY-CHAIN

KW - FOLLISTATIN-LIKE 1

KW - HEART-FAILURE

KW - NATRIURETIC-PEPTIDES

KW - EXPRESSION VARIATION

KW - ATRIAL-FIBRILLATION

U2 - 10.1186/s13059-017-1286-z

DO - 10.1186/s13059-017-1286-z

M3 - Article

C2 - 28903782

SN - 1474-7596

VL - 18

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 170

ER -

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

Abstract

Keywords

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