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

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 -