Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure

Marios Arvanitis, Emmanouil Tampakakis, Yanxiao Zhang, Wei Wang, Adam Auton, Diptavo Dutta, Stephanie Glavaris, Ali Keramati, Nilanjan Chatterjee, Neil C. Chi, Bing Ren, Wendy S. Post and Alexis Battle ()
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Marios Arvanitis: Johns Hopkins University
Emmanouil Tampakakis: Johns Hopkins University
Yanxiao Zhang: Ludwig Institute for Cancer Research
Wei Wang: 23andMe, Inc.
Adam Auton: 23andMe, Inc.
Diptavo Dutta: Johns Hopkins University
Stephanie Glavaris: Johns Hopkins University
Ali Keramati: Johns Hopkins University
Nilanjan Chatterjee: Johns Hopkins Bloomberg School of Public Health
Neil C. Chi: University of California, San Diego
Bing Ren: Ludwig Institute for Cancer Research
Wendy S. Post: Johns Hopkins University
Alexis Battle: Johns Hopkins University

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Heart failure is a major public health problem affecting over 23 million people worldwide. In this study, we present the results of a large scale meta-analysis of heart failure GWAS and replication in a comparable sized cohort to identify one known and two novel loci associated with heart failure. Heart failure sub-phenotyping shows that a new locus in chromosome 1 is associated with left ventricular adverse remodeling and clinical heart failure, in response to different initial cardiac muscle insults. Functional characterization and fine-mapping of that locus reveal a putative causal variant in a cardiac muscle specific regulatory region activated during cardiomyocyte differentiation that binds to the ACTN2 gene, a crucial structural protein inside the cardiac sarcolemma (Hi-C interaction p-value = 0.00002). Genome-editing in human embryonic stem cell-derived cardiomyocytes confirms the influence of the identified regulatory region in the expression of ACTN2. Our findings extend our understanding of biological mechanisms underlying heart failure.

Date: 2020
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DOI: 10.1038/s41467-020-14843-7

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