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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

European Heart Journal

3 March 2021
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ESC Journals ARRHYTHMIAS AND DEVICE THERAPY HEART FAILURE Chronic Heart Failure VALVULAR, MYOCARDIAL, PERICARDIAL, PULMONARY, CONGENITAL HEART DISEASE Myocardial Disease BASIC SCIENCE

Abstract

AbstractAims 

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.

Contributors

Sophie Garnier
Sophie Garnier

Author

Sorbonne University Paris , France

Author

Magdalena Harakalova
Magdalena Harakalova

Author

Author

Stefan Weiss
Stefan Weiss

Author

Author

Michal Mokry
Michal Mokry

Author

Author

Vera Regitz-Zagrosek
Vera Regitz-Zagrosek

Author

Author

Christian Hengstenberg
Christian Hengstenberg

Author

Medical University of Vienna Vienna , Austria

Author

Thomas P Cappola
Thomas P Cappola

Author

Author

Richard Isnard
Richard Isnard

Author

Author

Eloisa Arbustini
Eloisa Arbustini

Author

Foundation IRCCS Policlinic San Matteo - University of Pavia Pavia , Italy

Author

Stuart A Cook
Stuart A Cook

Author

Author

Jessica van Setten
Jessica van Setten

Author

Author

Jorg J A Calis
Jorg J A Calis

Author

Author

Hakon Hakonarson
Hakon Hakonarson

Author

Author

Michael P Morley
Michael P Morley

Author

Author

Klaus Stark
Klaus Stark

Author

Author

Sanjay K Prasad
Sanjay K Prasad

Author

Author

Jin Li
Jin Li

Author

Author

Declan P O'Regan
Declan P O'Regan

Author

Author

Maurizia Grasso
Maurizia Grasso

Author

Author

Martina Müller-Nurasyid
Martina Müller-Nurasyid

Author

Author

Thomas Meitinger
Thomas Meitinger

Author

Author

Jean-Philippe Empana
Jean-Philippe Empana

Author

National Institute of Health and Medical Research (INSERM home) Paris , France

Author

Konstantin Strauch
Konstantin Strauch

Author

Author

Melanie Waldenberger
Melanie Waldenberger

Author

Author

Kenneth B Marguiles
Kenneth B Marguiles

Author

Author

Christine E Seidman
Christine E Seidman

Author

Author

Georgios Kararigas
Georgios Kararigas

Author

Author

Benjamin Meder
Benjamin Meder

Author

Author

Jan Haas
Jan Haas

Author

Author

Pierre Boutouyrie
Pierre Boutouyrie

Author

Author

Patrick Lacolley
Patrick Lacolley

Author

Author

Xavier Jouven
Xavier Jouven

Author

Author

Jeanette Erdmann
Jeanette Erdmann

Author

Author

Stefan Blankenberg
Stefan Blankenberg

Author

Author

Thomas Wichter
Thomas Wichter

Author

Author

Volker Ruppert
Volker Ruppert

Author

Author

Luigi Tavazzi
Luigi Tavazzi

Author

Author

Olivier Dubourg
Olivier Dubourg

Author

Author

Gérard Roizes
Gérard Roizes

Author

Author

Richard Dorent
Richard Dorent

Author

Author

Pascal de Groote
Pascal de Groote

Author

Author

Laurent Fauchier
Laurent Fauchier

Author

University Hospital of Tours Tours , France

Author

Jean-Noël Trochu
Jean-Noël Trochu

Author

Author

Jean-François Aupetit
Jean-François Aupetit

Author

Author

Zofia T Bilinska
Zofia T Bilinska

Author

Author

Marine Germain
Marine Germain

Author

Author

Uwe Völker
Uwe Völker

Author

Author

Daiane Hemerich
Daiane Hemerich

Author

Author

Ibticem Raji
Ibticem Raji

Author

Author

Delphine Bacq-Daian
Delphine Bacq-Daian

Author

Author

Carole Proust
Carole Proust

Author

Author

Paloma Remior
Paloma Remior

Author

Author

Manuel Gomez-Bueno
Manuel Gomez-Bueno

Author

Author

Kristin Lehnert
Kristin Lehnert

Author

Universitaetsmedizin Greifswald Greifswald , Germany

Author

Renee Maas
Renee Maas

Author

Author

Robert Olaso
Robert Olaso

Author

Author

Ganapathi Varma Saripella
Ganapathi Varma Saripella

Author

Author

Stephan B Felix
Stephan B Felix

Author

Author

Steven McGinn
Steven McGinn

Author

Author

Laëtitia Duboscq-Bidot
Laëtitia Duboscq-Bidot

Author

Author

Alain van Mil
Alain van Mil

Author

Author

Céline Besse
Céline Besse

Author

Author

Vincent Fontaine
Vincent Fontaine

Author

Author

Hélène Blanché
Hélène Blanché

Author

Author

Flavie Ader
Flavie Ader

Author

Author

Brendan Keating
Brendan Keating

Author

Author

Angélique Curjol
Angélique Curjol

Author

Author

Anne Boland
Anne Boland

Author

Author

Michel Komajda
Michel Komajda

Author

Groupe Hospitalier Paris Saint-Joseph Paris , France

Author

François Cambien
François Cambien

Author

Author

Jean-François Deleuze
Jean-François Deleuze

Author

Author

Marcus Dörr
Marcus Dörr

Author

Author

Folkert W Asselbergs
Folkert W Asselbergs

Author

Author

Eric Villard
Eric Villard

Author

Author

David-Alexandre Trégouët
David-Alexandre Trégouët

Author

Author

Philippe Charron
Philippe Charron

Author

Pitie Salpetriere APHP University Hospital Paris , France

Author

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