Abstract
Idiopathic dilated cardiomyopathy (DCM) is a complex disorder with a genetic and an environmental component involving multiple genes, many of which are yet to be discovered. We integrate genetic, epigenetic, transcriptomic, phenotypic, and evolutionary features into a method – Hridaya, to infer putative functional genes underlying DCM in a genome-wide fashion, using 213 human heart genomes and transcriptomes. Many genes identified by Hridaya are experimentally shown to cause cardiac complications. We validate the top predicted genes, via five different genome-wide analyses: First, the predicted genes are associated with cardiovascular functions. Second, their knockdowns in mice induce cardiac abnormalities. Third, their inhibition by drugs cause cardiac side effects in human. Fourth, they tend to have differential exon usage between DCM and normal samples. Fifth, analyzing 213 individual genotypes, we show that regulatory polymorphisms of the predicted genes are associated with elevated risk of cardiomyopathy. The stratification of DCM patients based on cardiac expression of the functional genes reveals two subgroups differing in key cardiac phenotypes. Integrating predicted functional genes with cardiomyocyte drug treatment experiments reveals novel potential drug targets. We provide a list of investigational drugs that target the newly identified functional genes that may lead to cardiac side effects.
Highlights
Idiopathic dilated cardiomyopathy (DCM) is a complex disorder with a genetic and an environmental component involving multiple genes, many of which are yet to be discovered
DCM is a complex disorder caused by the dysregulation of multiple genes and is shown to have genetic basis[3]
Integrating genetic, epigenetic, transcriptomic, phenotypic, network, and evolutionary features (Supplementary Table S1), Hridaya hierarchically estimates the potential of a gene to be a functional gene of DCM in a supervised fashion (Fig. 1)
Summary
Idiopathic dilated cardiomyopathy (DCM) is a complex disorder with a genetic and an environmental component involving multiple genes, many of which are yet to be discovered. Epigenetic, transcriptomic, phenotypic, and evolutionary features into a method – Hridaya, to infer putative functional genes underlying DCM in a genome-wide fashion, using 213 human heart genomes and transcriptomes. We validate the top predicted genes, via five different genome-wide analyses: First, the predicted genes are associated with cardiovascular functions Their knockdowns in mice induce cardiac abnormalities. A recent paper[9] inferred gene co-expression network using diseased and healthy hearts and prioritized genes based on the differential network topology They identified PPP1R3A as a critical gene and experimentally verified its association with heart failure. The previous studies have not considered the genetic signals underlying the differentially expressed genes and the association of those signals with DCM to detect potentially functional genes. We train Hridaya using genetic, transcriptomic, and phenotypic data from 77 DCM human hearts and 136 human hearts from donor controls from the Myocardial Applied Genomics Network
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