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Integration of dilated cardiomyopathy genomics with transcriptomics from the human heart implicates regulatory
Connor S Murray1, Chaojie Yang1, Suet Nee Chen2
1Department of Genome Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
Insights
Researchers created the Trans-Omics for Precision Medicine in Congestive Heart Failure (TOPCHeF) resource, a multi-omics dataset, to uncover genetic links to heart failure (HF). This study identified key regulatory variants influencing gene expression and splicing in failing human hearts.
Area of Science:
- Genomics
- Cardiovascular Biology
- Molecular Mechanisms
Background:
- Heart failure (HF) is a major cause of death globally, but the molecular mechanisms connecting genetic variations to cardiac dysfunction are not fully understood.
- Understanding these mechanisms is crucial for developing targeted therapies and improving patient outcomes.
Purpose of the Study:
- To establish the Trans-Omics for Precision Medicine in Congestive Heart Failure (TOPCHeF) resource, a comprehensive multi-omics dataset.
- To identify regulatory molecular mechanisms, including expression and splicing quantitative trait loci (eQTLs and sQTLs), linking genetic variation to heart failure pathogenesis in human hearts.
Main Methods:
- Generated a multi-omics dataset from over 700 human left-ventricular tissue samples (dilated cardiomyopathy, ischemic cardiomyopathy, non-failing controls) with paired whole-genome and RNA sequencing.
- Mapped eQTLs and sQTLs directly in diseased human hearts to identify regulatory variants.
- Performed single-locus colocalization analysis with a large-scale dilated cardiomyopathy genome-wide association study.
Main Results:
- Identified over 10,000 transcripts with significant eQTLs and 8,600 isoforms with significant sQTLs in human hearts.
- Overlapped identified loci with previously known HF-associated regions and discovered novel gene associations.
- Confirmed 21 expression and 17 splicing-QTLs sharing causal variants with dilated cardiomyopathy risk, including known genes (e.g., FLNC, ACTN2) and novel candidates (e.g., CAMK2D, LMF1).
- Observed coordinated effects on gene expression and splicing, implicating calcium signaling, cytoskeletal organization, and metabolic pathways in HF.
Conclusions:
- The TOPCHeF resource provides a foundational dataset for understanding the regulatory landscape of the failing human heart.
- This study links genetic variation to specific transcriptional and splicing alterations, offering new insights into HF molecular mechanisms.
- Identified novel candidate genes and pathways involved in HF pathogenesis, paving the way for future research and therapeutic strategies.
Abstract:
Heart failure (HF) is a leading global cause of morbidity and mortality, yet the regulatory molecular mechanisms that link genetic variation to cardiac dysfunction remain elusive. To bridge this gap, we created the Trans-Omics for Precision Medicine in Congestive Heart Failure (TOPCHeF) resource, a multi-omics dataset comprising >700 human left-ventricular tissue samples, including dilated cardiomyopathy (DCM), ischemic cardiomyopathy (ICM), and non-failing controls, with paired whole-genome and RNA sequencing. By mapping expression- (eQTL) and splicing- (sQTL) quantitative trait loci directly in diseased human hearts, we identified over 10,000 transcripts with significant eQTL and 8,600 isoforms with significant sQTL, across both coding and non-coding genes, many of which overlap loci previously associated with HF and emerging novel gene associations. Single-locus colocalization with a largescale DCM genome-wide association study revealed 21 expression and 17 splicing-QTL that share causal variants with disease risk. These include known Mendelian cardiomyopathy risk genes such as FLNC and ACTN2, and novel regulatory candidates like CAMK2D, LMF1, MYOZ1, SKI, SYNPO2L, and TKT. Several loci also showed coordinated effects on both gene expression and RNA splicing, implicating calcium signaling, cytoskeletal organization, and metabolic pathways in HF pathogenesis. Together, these results help define the regulatory landscape of the failing human heart and establish TOPCHeF as a foundational resource for connecting genetic variation to transcriptional and splicing molecular mechanisms in HF research.
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