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

Garnier, Sophie; Harakalova, Magdalena; Weiss, Stefan; Mokry, Michal; Regitz-Zagrosek, Vera; Hengstenberg, Christian; Cappola, Thomas P.; Isnard, Richard; Arbustini, Eloisa; Cook, Stuart A.; Meitinger, Thomas; Charron, Philippe; Müller-Nurasyid, Martina und Strauch, Konstantin (2021): Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23. In: European Heart Journal

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 $\times$ 10-11 and 7.7 $\times$ 10-4 in the discovery and replication steps, respectively and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 $\times$ 10-8 and 1.4 $\times$ 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 27{\%} 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Bemerkung: Vollständige AutorInnen-Liste s. Volltext
• Sprache: Englisch