Integrative genomic and transcriptomic investigation of human heart failure mechanisms

Abstract: Heart failure (HF) is an expanding health problem, affecting >6.2M Americans, causing >80K deaths and >800K hospitalizations annually, and costing >$30B each year. HF is genetically complex as there are single- gene Mendelian (one mutation → causes disease) and disease susceptibility (several variants → influence risk of disease) models. The broad, long-term objective of our project is to use an integrated analysis approach to precisely quantify the contributions of rare Mendelian and more common disease susceptibility variants in dilated cardiomyopathy (DCM). Our project is responding to NOT-HL-23-067 (reissue of NOT-HL-21-017), Integrated Omics Analysis of NHLBI TOPMed Data, and targets the following key knowledge gaps: 1) how do rare Mendelian-disease and common complex-risk gene HF variants overlap and interact in the pathogenesis of HF, 2) which complex risk-variants are most likely to be functional (i.e. manifest specific biological mechanisms), and 3) what additional HF genes remain to be discovered (~50% of genetic HF lacks a pathogenic variant(s)). Our approach will leverage a unique whole-genome and whole-transcriptome human heart NHLBI- sequenced TOPMed dataset (~750 paired DNA/RNA sequenced human samples) using an integrated analysis approach to dissect the intersection of Mendelian and complex genes and variants. Building on these resources and approaches we will 1) validate which HR GWAS variants actually affect gene expression in the human heart, 2) discover novel human heart expression Quantitative Trait Loci (eQTL) from the cardiac transcriptome in health and disease, and 3) discover novel HR genes and pathways. Our hypotheses are 1) a subset of published GWAS HR variants exert direct eQTL mechanistic effects on gene expression in human cardiac tissue, 2) key genes and pathways of the HR transcriptome are mediated by novel genetic variants that have heretofore not been identified by GWAS approaches, and 3) integration of published Mendelian and GWAS HR variants in combination with cardiac tissue eQTL variants will reveal important, novel HR genes. Three Specific Aims to test these hypotheses are: 1) Map and validate published GWAS findings onto the human cardiac transcriptome, 2) Discover novel eQTL DNA variants from HR transcriptomes, and 3) Discover novel HR genes and perform functional validation studies in human heart tissue and hiPSC- cardiomyocytes. The impact of these studies will be a comprehensive genetic and RNA expression atlas of GWAS and eQTL biology in the human non-failing and failing heart models. This work will reveal and validate novel HR genes and pathways for the development of HR biomarkers and new treatment approaches.