Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23 - Université de Lorraine Access content directly
Journal Articles European Heart Journal Year : 2021

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

Sophie Garnier (1) , Magdalena Harakalova (2) , Stefan Weiss (3, 4) , Michal Mokry (2) , Vera Regitz-Zagrosek (5) , Christian Hengstenberg (4) , Thomas Cappola (6) , Richard Isnard (1) , Eloisa Arbustini (7) , Stuart Cook (8) , Jessica van Setten (2) , Jorg Calis (2) , Hakon Hakonarson (9) , Michael Morley (6) , Klaus Stark (10) , Sanjay Prasad (11) , Jin Li (9) , Declan O'Regan (12) , Maurizia Grasso (13) , Martina Müller-Nurasyid (14) , Thomas Meitinger (14, 15, 16) , Jean-Philippe Empana (1) , Konstantin Strauch (14, 15, 17) , Melanie Waldenberger (14, 4) , Kenneth Marguiles (18) , Christine Seidman (19) , Georgios Kararigas (20) , Benjamin Meder (21, 22) , Jan Haas (21) , Pierre Boutouyrie (1, 23) , Patrick Lacolley (24) , Xavier Jouven (1, 23) , Jeanette Erdmann (17) , Stefan Blankenberg (25) , Thomas Wichter (26) , Volker Ruppert (26) , Luigi Tavazzi (27) , Olivier Dubourg (28) , Gérard Roizes (29) , Richard Dorent (30) , Pascal de Groote (31) , Laurent Fauchier (32) , Jean-Noël Trochu (33) , Jean-François Aupetit (34) , Zofia Bilinska (35) , Marine Germain (36) , Uwe Völker (37, 4) , Daiane Hemerich (2) , Ibticem Raji (38) , Delphine Bacq-Daian (39, 40) , Carole Proust (36) , Paloma Remior (41) , Manuel Gomez-Bueno (41) , Kristin Lehnert (3, 4) , Renee Maas (2) , Robert Olaso (39, 40) , Ganapathi Varma Saripella (42, 1) , Stephan Felix (4, 3) , Steven Mcginn (39, 40) , Laëtitia Duboscq-Bidot (1) , Alain van Mil (2) , Céline Besse (39, 40) , Vincent Fontaine (1) , Hélène Blanché (40, 43) , Flavie Ader (1, 44, 45) , Brendan Keating (6) , Angélique Curjol (38) , Anne Boland (39, 40) , Michel Komajda (46, 1) , François Cambien (36) , Jean-François Deleuze (39, 40, 47) , Marcus Dörr (4, 3) , Folkert Asselbergs (2, 48) , Eric Villard (1) , David-Alexandre Trégouët (36, 40) , Philippe Charron (1, 44, 38)
1 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
2 UMCU - University Medical Center [Utrecht]
3 Universität Greifswald - University of Greifswald
4 DZHK - German Center for Cardiovascular Research
5 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
6 University of Pennsylvania
7 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico
8 NHCS - National Heart Centre Singapore
9 CHOP - Children’s Hospital of Philadelphia
10 University of Regensburg
11 Royal Brompton Hospital
12 Imperial College London
13 IRCCS Pavia - ICS Maugeri - Istituti Clinici Scientifici Maugeri [Pavia]
14 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
15 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
16 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
17 University Medical Center of the Johannes Gutenberg-University Mainz
18 Perelman School of Medicine
19 HMS - Harvard Medical School [Boston]
20 University of Iceland [Reykjavik]
21 Universität Heidelberg [Heidelberg] = Heidelberg University
22 Stanford University
23 HEGP - Hôpital Européen Georges Pompidou [APHP]
24 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
25 Universität zu Lübeck = University of Lübeck [Lübeck]
26 Universitätklinikum Gießen und Marburg GmbH
27 Maria Cecilia Hospital
28 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
29 IGH - Institut de génétique humaine
30 CHU Tenon [AP-HP]
31 Hôpital cardiologique
32 CHU Trousseau [Tours]
33 ITX - ITX - unité de recherche de l'institut du thorax
34 Centre hospitalier Saint Joseph - Saint Luc [Lyon]
35 National Institute of Cardiology [Varsovie, Pologne]
36 BPH - Bordeaux population health
37 University of Medicine Greifswald
38 Centre de Référence Maladies Cardiaques Héréditaires
39 CNRGH - Centre National de Recherche en Génomique Humaine
40 Medical Genomics - Laboratory of Excellence GENMED [Paris]
41 Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain]
42 SLU - Swedish University of Agricultural Sciences = Sveriges lantbruksuniversitet
43 CEPH - Centre d'Etude du Polymorphisme Humain
44 CHU Pitié-Salpêtrière [AP-HP]
45 UPD5 Pharmacie - Faculté de Pharmacie de Paris - Université Paris Descartes
46 Groupe Hospitalier Paris Saint Joseph
47 CEPH - Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris]
48 UCL - University College of London [London]
Michal Mokry
Jessica van Setten
Jorg Calis
Hakon Hakonarson
Klaus Stark
Georgios Kararigas
Gérard Roizes
Richard Dorent
Laurent Fauchier
Daiane Hemerich
Alain van Mil

Abstract

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.

Dates and versions

hal-03567179 , version 1 (11-02-2022)

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Sophie Garnier, Magdalena Harakalova, Stefan Weiss, Michal Mokry, Vera Regitz-Zagrosek, et al.. 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, 2021, 42 (20), pp.2000-2011. ⟨10.1093/eurheartj/ehab030⟩. ⟨hal-03567179⟩
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