Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
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Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23. / Garnier, Sophie; Harakalova, Magdalena; Weiss, Stefan; Mokry, Michal; Regitz-Zagrosek, Vera; Hengstenberg, Christian; Cappola, Thomas P; Isnard, Richard; Arbustini, Eloisa; Cook, Stuart A; van Setten, Jessica; Calis, Jorg J A; Hakonarson, Hakon; Morley, Michael P; Stark, Klaus; Prasad, Sanjay K; Li, Jin; O'Regan, Declan P; Grasso, Maurizia; Müller-Nurasyid, Martina; Meitinger, Thomas; Empana, Jean-Philippe; Strauch, Konstantin; Waldenberger, Melanie; Marguiles, Kenneth B; Seidman, Christine E; Kararigas, Georgios; Meder, Benjamin; Haas, Jan; Boutouyrie, Pierre; Lacolley, Patrick; Jouven, Xavier; Erdmann, Jeanette; Blankenberg, Stefan; Wichter, Thomas; Ruppert, Volker; Tavazzi, Luigi; Dubourg, Olivier; Roizes, Gérard; Dorent, Richard; de Groote, Pascal; Fauchier, Laurent; Trochu, Jean-Noël; Aupetit, Jean-François; Bilinska, Zofia T; Germain, Marine; Völker, Uwe; Hemerich, Daiane; Raji, Ibticem; Bacq-Daian, Delphine; Proust, Carole; Remior, Paloma; Gomez-Bueno, Manuel; Lehnert, Kristin; Maas, Renee; Olaso, Robert; Saripella, Ganapathi Varma; Felix, Stephan B; McGinn, Steven; Duboscq-Bidot, Laëtitia; van Mil, Alain; Besse, Céline; Fontaine, Vincent; Blanché, Hélène; Ader, Flavie; Keating, Brendan; Curjol, Angélique; Boland, Anne; Komajda, Michel; Cambien, François; Deleuze, Jean-François; Dörr, Marcus; Asselbergs, Folkert W; Villard, Eric; Trégouët, David-Alexandre; Charron, Philippe.
in: EUR HEART J, Jahrgang 42, Nr. 20, 21.05.2021, S. 2000-2011.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
AU - Garnier, Sophie
AU - Harakalova, Magdalena
AU - Weiss, Stefan
AU - Mokry, Michal
AU - Regitz-Zagrosek, Vera
AU - Hengstenberg, Christian
AU - Cappola, Thomas P
AU - Isnard, Richard
AU - Arbustini, Eloisa
AU - Cook, Stuart A
AU - van Setten, Jessica
AU - Calis, Jorg J A
AU - Hakonarson, Hakon
AU - Morley, Michael P
AU - Stark, Klaus
AU - Prasad, Sanjay K
AU - Li, Jin
AU - O'Regan, Declan P
AU - Grasso, Maurizia
AU - Müller-Nurasyid, Martina
AU - Meitinger, Thomas
AU - Empana, Jean-Philippe
AU - Strauch, Konstantin
AU - Waldenberger, Melanie
AU - Marguiles, Kenneth B
AU - Seidman, Christine E
AU - Kararigas, Georgios
AU - Meder, Benjamin
AU - Haas, Jan
AU - Boutouyrie, Pierre
AU - Lacolley, Patrick
AU - Jouven, Xavier
AU - Erdmann, Jeanette
AU - Blankenberg, Stefan
AU - Wichter, Thomas
AU - Ruppert, Volker
AU - Tavazzi, Luigi
AU - Dubourg, Olivier
AU - Roizes, Gérard
AU - Dorent, Richard
AU - de Groote, Pascal
AU - Fauchier, Laurent
AU - Trochu, Jean-Noël
AU - Aupetit, Jean-François
AU - Bilinska, Zofia T
AU - Germain, Marine
AU - Völker, Uwe
AU - Hemerich, Daiane
AU - Raji, Ibticem
AU - Bacq-Daian, Delphine
AU - Proust, Carole
AU - Remior, Paloma
AU - Gomez-Bueno, Manuel
AU - Lehnert, Kristin
AU - Maas, Renee
AU - Olaso, Robert
AU - Saripella, Ganapathi Varma
AU - Felix, Stephan B
AU - McGinn, Steven
AU - Duboscq-Bidot, Laëtitia
AU - van Mil, Alain
AU - Besse, Céline
AU - Fontaine, Vincent
AU - Blanché, Hélène
AU - Ader, Flavie
AU - Keating, Brendan
AU - Curjol, Angélique
AU - Boland, Anne
AU - Komajda, Michel
AU - Cambien, François
AU - Deleuze, Jean-François
AU - Dörr, Marcus
AU - Asselbergs, Folkert W
AU - Villard, Eric
AU - Trégouët, David-Alexandre
AU - Charron, Philippe
N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
PY - 2021/5/21
Y1 - 2021/5/21
N2 - 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 3-fold 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.
AB - 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 3-fold 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.
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Animals
KW - Apoptosis Regulatory Proteins
KW - Cardiomyopathy, Dilated/genetics
KW - Chromosomes
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study
KW - Heart Failure, Systolic/genetics
KW - Humans
KW - Polymorphism, Single Nucleotide/genetics
U2 - 10.1093/eurheartj/ehab030
DO - 10.1093/eurheartj/ehab030
M3 - SCORING: Journal article
C2 - 33677556
VL - 42
SP - 2000
EP - 2011
JO - EUR HEART J
JF - EUR HEART J
SN - 0195-668X
IS - 20
ER -