Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure.
ABO Blood-Group System
/ genetics
Actinin
/ genetics
Atrial Fibrillation
/ genetics
Chromosomes, Human, Pair 1
Enhancer Elements, Genetic
Gene Expression Regulation
Genetic Predisposition to Disease
/ genetics
Genome-Wide Association Study
Heart Failure
/ genetics
Human Embryonic Stem Cells
/ cytology
Humans
Musculoskeletal Diseases
/ genetics
Myocytes, Cardiac
/ cytology
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 02 2020
28 02 2020
Historique:
received:
02
08
2019
accepted:
27
01
2020
entrez:
1
3
2020
pubmed:
1
3
2020
medline:
27
5
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32111823
doi: 10.1038/s41467-020-14843-7
pii: 10.1038/s41467-020-14843-7
pmc: PMC7048760
doi:
Substances chimiques
ABO Blood-Group System
0
ACTN2 protein, human
0
Actinin
11003-00-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1122Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : T32-HL007227
Pays : International
Organisme : NHGRI NIH HHS
ID : R01 HG010480
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : K08- HL145135-01
Pays : International
Organisme : U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
ID : R01-HG010480-01
Pays : International
Organisme : American Heart Association (American Heart Association, Inc.)
ID : 19CDA34660077
Pays : International
Organisme : NHLBI NIH HHS
ID : K08 HL145135
Pays : United States
Investigateurs
Michelle Agee
(M)
Stella Aslibekyan
(S)
Robert K Bell
(RK)
Katarzyna Bryc
(K)
Sarah K Clark
(SK)
Sarah L Elson
(SL)
Kipper Fletez-Brant
(K)
Pierre Fontanillas
(P)
Nicholas A Furlotte
(NA)
Pooja M Gandhi
(PM)
Karl Heilbron
(K)
Barry Hicks
(B)
David A Hinds
(DA)
Karen E Huber
(KE)
Ethan M Jewett
(EM)
Yunxuan Jiang
(Y)
Aaron Kleinman
(A)
Keng-Han Lin
(KH)
Nadia K Litterman
(NK)
Jennifer C McCreight
(JC)
Matthew H McIntyre
(MH)
Kimberly F McManus
(KF)
Joanna L Mountain
(JL)
Sahar V Mozaffari
(SV)
Priyanka Nandakumar
(P)
Elizabeth S Noblin
(ES)
Carrie A M Northover
(CAM)
Jared O'Connell
(J)
Steven J Pitts
(SJ)
G David Poznik
(GD)
J Fah Sathirapongsasuti
(JF)
Anjali J Shastri
(AJ)
Janie F Shelton
(JF)
Suyash Shringarpure
(S)
Chao Tian
(C)
Joyce Y Tung
(JY)
Robert J Tunney
(RJ)
Vladimir Vacic
(V)
Xin Wang
(X)
Amir S Zare
(AS)
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