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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

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, 49, 38
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.
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Submitted on : Friday, February 11, 2022 - 9:39:28 PM
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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, Oxford University Press (OUP): Policy B, 2021, 42 (20), pp.2000-2011. ⟨10.1093/eurheartj/ehab030⟩. ⟨hal-03567179⟩

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