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, Michelle Agee, Stella Aslibekyan, Robert K. Bell, Katarzyna Bryc, Sarah Clark, Sarah L. Elson, Kipper Fletez‐Brant, Pierre Fontanillas, Nicholas A. Furlotte, Pooja Gandhi, Karl Heilbron, Barry Hicks, David A. Hinds, Karen E. Huber, Ethan M. Jewett, Yunxuan Jiang, Aaron Kleinman, Keng‐Han Lin, Nadia K. Litterman, Jennifer C. McCreight, Matthew H. McIntyre, Kimberly F. McManus, Joanna L. Mountain, Sahar V. Mozaffari, Priyanka Nandakumar, Elizabeth S. Noblin, Carrie A. M. Northover, Jared O’Connell, Steven J. Pitts, G. David Poznik, J. Fah Sathirapongsasuti, Anjali J. Shastri, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Robert J. Tunney, Vladimir Vacic, Xin Wang, Amir S. Zare, Diptavo Dutta, Stephanie Glavaris, Ali R. Keramati, Nilanjan Chatterjee, C. Neil, Bing Ren, Wendy S. Post, Alexis Battle
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.