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

Title: Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy
Authors: Heinig, M
Adriaens, ME
Schafer, S
Van Deutekom, HWM
Lodder, EM
Ware, JS
Schneider, V
Felkin, LE
Creemers, EE
Meder, B
Katus, HA
Ruehle, 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
Rueschendorf, F
Rintisch, C
Petretto, E
Barton, PJ
Cook, SA
Pinto, YM
Bezzina, CR
Hubner, N
Item Type: Journal Article
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.
Issue Date: 14-Sep-2017
Date of Acceptance: 19-Jul-2017
URI: http://hdl.handle.net/10044/1/51162
DOI: https://dx.doi.org/10.1186/s13059-017-1286-z
ISSN: 1474-7596
Publisher: BioMed Central
Journal / Book Title: Genome Biology
Volume: 18
Copyright Statement: © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Wellcome Trust
Fondation Leducq
Funder's Grant Number: 107469/Z/15/Z
16 CVD 03
Keywords: Science & Technology
Life Sciences & Biomedicine
Biotechnology & Applied Microbiology
Genetics & Heredity
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
05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Bioinformatics
Publication Status: Published
Article Number: 170
Appears in Collections:Clinical Sciences
National Heart and Lung Institute
Molecular Sciences
Faculty of Medicine



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