TY - JOUR
T1 - Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure
AU - 23andMe Research Team
AU - Arvanitis, Marios
AU - Tampakakis, Emmanouil
AU - Zhang, Yanxiao
AU - Wang, Wei
AU - Auton, Adam
AU - Agee, Michelle
AU - Aslibekyan, Stella
AU - Bell, Robert K.
AU - Bryc, Katarzyna
AU - Clark, Sarah K.
AU - Elson, Sarah L.
AU - Fletez-Brant, Kipper
AU - Fontanillas, Pierre
AU - Furlotte, Nicholas A.
AU - Gandhi, Pooja M.
AU - Heilbron, Karl
AU - Hicks, Barry
AU - Hinds, David A.
AU - Huber, Karen E.
AU - Jewett, Ethan M.
AU - Jiang, Yunxuan
AU - Kleinman, Aaron
AU - Lin, Keng Han
AU - Litterman, Nadia K.
AU - McCreight, Jennifer C.
AU - McIntyre, Matthew H.
AU - McManus, Kimberly F.
AU - Mountain, Joanna L.
AU - Mozaffari, Sahar V.
AU - Nandakumar, Priyanka
AU - Noblin, Elizabeth S.
AU - Northover, Carrie A.M.
AU - O’Connell, Jared
AU - Pitts, Steven J.
AU - Poznik, G. David
AU - Sathirapongsasuti, J. Fah
AU - Shastri, Anjali J.
AU - Shelton, Janie F.
AU - Shringarpure, Suyash
AU - Tian, Chao
AU - Tung, Joyce Y.
AU - Tunney, Robert J.
AU - Vacic, Vladimir
AU - Wang, Xin
AU - Zare, Amir S.
AU - Dutta, Diptavo
AU - Glavaris, Stephanie
AU - Keramati, Ali
AU - Chatterjee, Nilanjan
AU - Post, Wendy S.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-14843-7
DO - 10.1038/s41467-020-14843-7
M3 - Article
C2 - 32111823
AN - SCOPUS:85081023605
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1122
ER -