Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
Authors: Garnier Sophie , Harakalova Magdalena , Weiss Stefan , Mokry Michal , Regitz-Zagrosek Vera , Hengstenberg Christian , Cappola Thomas P , Isnard Richard , Arbustini Eloisa , Cook Stuart A , van Setten Jessica , Calis Jorg J A , Hakonarson Hakon , Morley Michael P , Stark Klaus , Prasad Sanjay K , Li Jin , O'Regan Declan P , Grasso Maurizia , Müller-Nurasyid Martina , Meitinger Thomas , Empana Jean-Philippe , Strauch Konstantin , Waldenberger Melanie , Marguiles Kenneth B , Seidman Christine E , Kararigas Georgios , Meder Benjamin , Haas Jan , Boutouyrie Pierre , Lacolley Patrick , Jouven Xavier , Erdmann Jeanette , Blankenberg Stefan , Wichter Thomas , Ruppert Volker , Tavazzi Luigi , Dubourg Olivier , Roizes Gérard , Dorent Richard , de Groote Pascal , Fauchier Laurent , Trochu Jean-Noël , Aupetit Jean-François , Bilinska Zofia T , Germain Marine , Völker Uwe , Hemerich Daiane , Raji Ibticem , Bacq-Daian Delphine , Proust Carole , Remior Paloma , Gomez-Bueno Manuel , Lehnert Kristin , Maas Renee , Olaso Robert , Saripella Ganapathi Varma , Felix Stephan B , McGinn Steven , Duboscq-Bidot Laëtitia , van Mil Alain , Besse Céline , Fontaine Vincent , Blanché Hélène , Ader Flavie , Keating Brendan , Curjol Angélique , Boland Anne , Komajda Michel , Cambien François , Deleuze Jean-François , Dörr Marcus , Asselbergs Folkert W , Villard Eric , Trégouët David-Alexandre , Charron Philippe 
Published: January 2021

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.