Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

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Title: Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy
Author(s): Esslinger, U
Garnier, S
Korniat, A
Proust, C
Kararigas, G
Mueller-Nurasyid, M
Empana, J-P
Morley, MP
Perret, C
Stark, K
Bick, AG
Prasad, SK
Kriebel, J
Li, J
Tiret, L
Strauch, K
O'Regan, DP
Marguiles, KB
Seidman, JG
Boutouyrie, P
Lacolley, P
Jouven, X
Hengstenberg, C
Komajda, M
Hakonarson, H
Isnard, R
Arbustini, E
Grallert, H
Cook, SA
Seidman, CE
Regitz-Zagrosek, V
Cappola, TP
Charron, P
Cambien, F
Villard, E
Item Type: Journal Article
Abstract: Aims: Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results: 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. Conclusion: We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.
Publication Date: 15-Mar-2017
Date of Acceptance: 13-Feb-2017
URI: http://hdl.handle.net/10044/1/45990
DOI: https://dx.doi.org/10.1371/journal.pone.0172995
ISSN: 1932-6203
Publisher: PUBLIC LIBRARY OF SCIENCE
Journal / Book Title: PLOS ONE
Volume: 12
Issue: 3
Copyright Statement: © 2017 The Author(s). This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmi tted, modifie d, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
Sponsor/Funder: Fondation Leducq
National Institute for Health Research
British Heart Foundation
Wellcome Trust
Department of Health
Funder's Grant Number: 11 CVD-01
RDB02 79560
PG/12/27/29489
HICF-R6-373
HICF-R6-373
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
SKELETAL-MUSCLES
COMMON VARIANTS
HEART-FAILURE
P19CL6 CELLS
PROTEIN
MUTATIONS
HSPB7
FHOD3
DIFFERENTIATION
ARCHITECTURE
General Science & Technology
MD Multidisciplinary
Publication Status: Published
Article Number: ARTN e0172995
Open Access location: http://dx.doi.org/10.1371/journal.pone.0172995
Appears in Collections:Clinical Sciences
Imaging Sciences
National Heart and Lung Institute



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