Integrative genetic and network approaches to identify key regulators of cardiac fibrosis

Abstract

Excessive fibrogenic response is a pathological hallmark of chronic complex diseases, including cardiovascular disease. To date, very few gene targets for cardiac fibrosis that led to effective treatments have been identified in humans. In this thesis I study and dissect the genetic component underlying cardiac fibrosis. This study integrates histomorphometric measurements of fibrosis in the rat left ventricle (LV) with gene expression (RNA-Seq from LV) and genetic data in a panel of recombinant inbred (RI) rat strains (n=30). In addition, I integrated RNA-seq LV and genetic data in humans (n=187, healthy and dilated cardiomyopathy (DCM) patients), as well as DCM genome-wide association studies (GWAS) data. I started by carrying out an unbiased co-expression network analysis in the rat heart. The reconstructed cardiac transcriptional modules were associated with quantitative levels of fibrosis. Co-expression networks were also independently built in the heart of DCM patients and by using the rat data, co-expression networks associated with fibrosis, conserved across rats and humans and not present in control human heart were prioritised. In the prioritised networks, I also analysed their cardiac cell type specificity, differential expression after TGFβ induction, potential driving transcription factors and conservation in other fibrotic diseases by analysing human data collected from other organs. Furthermore, I aimed to identify common genetic regulators of the networks (also called master genetic regulators) by using Bayesian multivariate regression approaches. Finally, I integrated GWAS data in DCM (n=2,287) to dissect the genetic basis of DCM. This systems genetics study evidences that there are transcriptional processes involved in the human cardiac fibrogenic response that are conserved across rats and humans, some of them also underlying DCM aetiology. In an attempt to suggest new gene targets for cardiac fibrosis, I also identified the WWP2 gene as a novel trans-acting genetic regulator of cardiac fibrosis.