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
N1 - Publisher Copyright:
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 - 4C-sequencing
KW - Genetic risk score
KW - GWAS
KW - Heart failure
KW - Imputation
KW - Dilated cardiomyopathy
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U2 - 10.1093/eurheartj/ehab030
DO - 10.1093/eurheartj/ehab030
M3 - Article
C2 - 33677556
AN - SCOPUS:85107088179
VL - 42
SP - 2000
EP - 2011
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 20
ER -