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Garnier, S.* ; Harakalova, M.* ; Weiss, S.* ; Mokry, M.* ; Regitz-Zagrosek, V.* ; Hengstenberg, C.* ; Cappola, T.P.* ; Isnard, R.* ; Arbustini, E.* ; Cook, S.A.* ; van Setten, J.* ; Calis, J.J.A.* ; Hakonarson, H.* ; Morley, M.P.* ; Stark, K.* ; Prasad, S.K.* ; Li, J.* ; O'Regan, D.P.* ; Grasso, M.* ; Müller-Nurasyid, M. ; Meitinger, T. ; Empana, J.P.* ; Strauch, K. ; Waldenberger, M. ; Marguiles, K.B.* ; Seidman, C.E.* ; Kararigas, G.* ; Meder, B.* ; Haas, J.* ; Boutouyrie, P.* ; Lacolley, P.* ; Jouven, X.* ; Erdmann, J.* ; Blankenberg, S.* ; Wichter, T.* ; Ruppert, V.* ; Tavazzi, L.* ; Dubourg, O.* ; Roizes, G.* ; Dorent, R.* ; de Groote, P.* ; Fauchier, L.* ; Trochu, J.N.* ; Aupetit, J.F.* ; Bilinska, Z.T.* ; Germain, M.* ; Völker, U.* ; Hemerich, D.* ; Raji, I.* ; Bacq-Daian, D.* ; Proust, C.* ; Remior, P.* ; Gomez-Bueno, M.* ; Lehnert, K.* ; Maas, R.* ; Olaso, R.* ; Saripella, G.V.* ; Felix, S.B.* ; McGinn, S.* ; Duboscq-Bidot, L.* ; van Mil, A.* ; Besse, C.* ; Fontaine, V.* ; Blanché, H.* ; Ader, F.* ; Keating, B.* ; Curjol, A.* ; Boland, A.* ; Komajda, M.* ; Cambien, F.* ; Deleuze, J.F.* ; Dörr, M.* ; Asselbergs, F.W.* ; Villard, E.* ; Trégouët, D.A.* ; Charron, P.*

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Eur. Heart J. 42, 2000-2011 (2021)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
AIMS : Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS : We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION : This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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Publication type Article: Journal article
Document type Scientific Article
Keywords 4c-sequencing ; Gwas ; Genetic Risk Score ; Heart Failure ; Imputation ;  dilated Cardiomyopathy; Taurine
ISSN (print) / ISBN 0195-668X
e-ISSN 1522-9645
Quellenangaben Volume: 42, Issue: 20, Pages: 2000-2011 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Reviewing status Peer reviewed
Grants British Heart Foundation
Social Ministry of the Federal State of Mecklenburg-West Pomerania
Ministry of Cultural Affairs
Federal Ministry of Education and Research
Societe Francaise de Cardiologie/Federation Francaise de Cardiologie
PROMEX charitable foundation
'Fondation LEDUCQ' [Eurogene Heart Failure network]
Dele gation a la recherche clinique AP-HP
Assistance Publique-Hopitaux de Paris [PHRC programme hospitalier de recherche Clinique]
DETECTIN-HF project
German Center for Cardiovascular Research (DZHK)
Helmholtz Zentrum Munchen -German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
State of Bavaria
National Institute for Health Research (NIHR) Imperial College Biomedical Research Centre
Medical Research Council, UK
"EPIDEMIOM-VTE" Senior Chair from the Initiative of Excellence of the University of Bordeaux
NWO VENI grant
UCL Hospitals NIHR Biomedical Research Centre
Else Kroner Fresenius Foundation
Deutsche Forschungsgemeinschaft (DFG)
Informatics for Life (Klaus Tschira Foundation)
German Ministry of Education and Research [CaRNAtion]
Deutsches Zentrum fur Herz-Kreislauf-Forschung (German Center for Cardiovascular Research, DZHK)
Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ
GENMED Laboratory of Excellence on Medical Genomics