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

Sophie Garnier; Magdalena Harakalova; Stefan Weiss; Michal Mokry; Vera Regitz-Zagrosek; Christian Hengstenberg; Thomas P. Cappola; Richard Isnard; Eloisa Arbustini; Stuart A. Cook; Jessica van Setten; Jorg J.A. Calis; Hakon Hakonarson; Michael P. Morley; Klaus Stark; Sanjay K. Prasad; Jin Li; Declan P. O’Regan; Maurizia Grasso; Martina Müller-Nurasyid; Thomas Meitinger; Jean Philippe Empana; Konstantin Strauch; Melanie Waldenberger; Kenneth B. Marguiles; Christine E. Seidman; Benjamin Meder; Jan Haas; Pierre Boutouyrie; Patrick Lacolley; Xavier Jouven; Jeanette Erdmann; Stefan Blankenberg; Thomas Wichter; Volker Ruppert; Luigi Tavazzi; Olivier Dubourg; Gérard Roizes; Richard Dorent; Pascal de Groote; Laurent Fauchier; Jean Noël Trochu; Jean François Aupetit; Zofia T. Bilinska; Marine Germain; Uwe Völker; Daiane Hemerich; Ibticem Raji; Delphine Bacq-Daian

doi:10.1093/eurheartj/ehab030

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

Sophie Garnier
, Magdalena Harakalova
, Stefan Weiss
, Michal Mokry
, Vera Regitz-Zagrosek
, Christian Hengstenberg
, Thomas P. Cappola
, Richard Isnard
, Eloisa Arbustini
, Stuart A. Cook
, Jessica van Setten
, Jorg J.A. Calis
, Hakon Hakonarson
, Michael P. Morley
, Klaus Stark
, Sanjay K. Prasad
, Jin Li
, Declan P. O’Regan
, Maurizia Grasso
, Martina Müller-Nurasyid

Thomas Meitinger, Jean Philippe Empana, Konstantin Strauch, Melanie Waldenberger, Kenneth B. Marguiles, Christine E. Seidman, Benjamin Meder, Jan Haas, Pierre Boutouyrie, Patrick Lacolley, Xavier Jouven, Jeanette Erdmann, Stefan Blankenberg, Thomas Wichter, Volker Ruppert, Luigi Tavazzi, Olivier Dubourg, Gérard Roizes, Richard Dorent, Pascal de Groote, Laurent Fauchier, Jean Noël Trochu, Jean François Aupetit, Zofia T. Bilinska, Marine Germain, Uwe Völker, Daiane Hemerich, Ibticem Raji, Delphine Bacq-Daian

Faculty of Medicine

University of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	2000-2011
Number of pages	12
Journal	European heart journal
Volume	42
Issue number	20
DOIs	https://doi.org/10.1093/eurheartj/ehab030
Publication status	Published - 3 Mar 2021

Bibliographical note

Other keywords

Adaptor Proteins, Signal Transducing/genetics
Animals
Apoptosis Regulatory Proteins
Cardiomyopathy, Dilated/genetics
Cardiomyopathy, delated
Chromosomes
Genetic Predisposition to Disease/genetics
Genetics
Genome-Wide Association Study
Heart Failure, Systolic/genetics
Heart failure, systolic
Humans
Polymorphism, Single Nucleotide/genetics

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10.1093/eurheartj/ehab030

Cite this

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., ... Bacq-Daian, D. (2021). Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23. European heart journal, 42(20), 2000-2011. https://doi.org/10.1093/eurheartj/ehab030

@article{8b995e8b9390493485ef121bfc91af86,

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

abstract = "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.",

keywords = "Adaptor Proteins, Signal Transducing/genetics, Animals, Apoptosis Regulatory Proteins, Cardiomyopathy, Dilated/genetics, Cardiomyopathy, delated, Chromosomes, Genetic Predisposition to Disease/genetics, Genetics, Genome-Wide Association Study, Heart Failure, Systolic/genetics, Heart failure, systolic, Humans, Polymorphism, Single Nucleotide/genetics",

author = "Sophie Garnier and Magdalena Harakalova and Stefan Weiss and Michal Mokry and Vera Regitz-Zagrosek and Christian Hengstenberg and Cappola, \{Thomas P.\} and Richard Isnard and Eloisa Arbustini and Cook, \{Stuart A.\} and \{van Setten\}, Jessica and Calis, \{Jorg J.A.\} and Hakon Hakonarson and Morley, \{Michael P.\} and Klaus Stark and Prasad, \{Sanjay K.\} and Jin Li and O{\textquoteright}Regan, \{Declan P.\} and Maurizia Grasso and Martina M{\"u}ller-Nurasyid and Thomas Meitinger and Empana, \{Jean Philippe\} and Konstantin Strauch and Melanie Waldenberger and Marguiles, \{Kenneth B.\} and Seidman, \{Christine E.\} and Benjamin Meder and Jan Haas and Pierre Boutouyrie and Patrick Lacolley and Xavier Jouven and Jeanette Erdmann and Stefan Blankenberg and Thomas Wichter and Volker Ruppert and Luigi Tavazzi and Olivier Dubourg and G{\'e}rard Roizes and Richard Dorent and \{de Groote\}, Pascal and Laurent Fauchier and Trochu, \{Jean No{\"e}l\} and Aupetit, \{Jean Fran{\c c}ois\} and Bilinska, \{Zofia T.\} and Marine Germain and Uwe V{\"o}lker and Daiane Hemerich and Ibticem Raji and Delphine Bacq-Daian",

year = "2021",

month = mar,

day = "3",

doi = "10.1093/eurheartj/ehab030",

language = "English",

volume = "42",

pages = "2000--2011",

journal = "European heart journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "20",

}

Garnier, S, Harakalova, M, Weiss, S, Mokry, M, Regitz-Zagrosek, V, Hengstenberg, C, Cappola, TP, Isnard, R, Arbustini, E, Cook, SA, van Setten, J, Calis, JJA, Hakonarson, H, Morley, MP, Stark, K, Prasad, SK, Li, J, O’Regan, DP, Grasso, M, Müller-Nurasyid, M, Meitinger, T, Empana, JP, Strauch, K, Waldenberger, M, Marguiles, KB, Seidman, CE, 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, JN, Aupetit, JF, Bilinska, ZT, Germain, M, Völker, U, Hemerich, D, Raji, I & Bacq-Daian, D 2021, 'Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23', European heart journal, vol. 42, no. 20, pp. 2000-2011. https://doi.org/10.1093/eurheartj/ehab030

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 - 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

PY - 2021/3/3

Y1 - 2021/3/3

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 - Cardiomyopathy, delated

KW - Chromosomes

KW - Genetic Predisposition to Disease/genetics

KW - Genetics

KW - Genome-Wide Association Study

KW - Heart Failure, Systolic/genetics

KW - Heart failure, systolic

KW - Humans

KW - Polymorphism, Single Nucleotide/genetics

UR - https://www.scopus.com/pages/publications/85107088179

U2 - 10.1093/eurheartj/ehab030

DO - 10.1093/eurheartj/ehab030

M3 - Article

C2 - 33677556

SN - 0195-668X

VL - 42

SP - 2000

EP - 2011

JO - European heart journal

JF - European heart journal

IS - 20

ER -

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

Abstract

Bibliographical note

Other keywords

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