What is the clinical evidence from this study?

Study design: Observational. Population: Dilated cardiomyopathy (n=205). Primary outcome: Differential gene expression and splicing between DCM and donor samples.

What does this research mean for the field?

Genetic variation exerts widespread effects on RNA transcription and splicing in dilated cardiomyopathy, driving extensive differences in the expression of protein-coding genes compared to non-diseased hearts. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

September 11, 2017Open Access

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

Key Result

RNA-sequencing of left ventricular tissue revealed 228 differentially expressed protein-coding genes and widespread effects of genetic variation on transcription and splicing in dilated cardiomyopathy.

Study Design

Type

Observational (n=205)

Multicenter

Yes

Structured PICO

Population

97 patients with dilated cardiomyopathy and 108 non-diseased controls

Comparator

108 non-diseased controls

Outcome

Differences in gene expression, alternative splicing, and allele-specific expression between DCM patients and controls, and identification of eQTLs and sQTLssurrogate

RNA transcription, splicing, and allele-specific expression are significantly altered in dilated cardiomyopathy and are strongly controlled by genetic factors, providing a resource for cardiovascular genetics.

Limitations

DCM cases and non-diseased controls were not recruited in the same centers
Sequencing was not performed in mixed runs
Both populations were not deeply phenotyped
Samples were collected at different centers and sequenced over an extended period in a non-randomized order, which could lead to confounding

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.

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