6533b85afe1ef96bd12b963a
RESEARCH PRODUCT
Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
Magdalena HarakalovaBenjamin MederBenjamin MederPhilippe CharronManuel Gómez-buenoJorg J. A. CalisFrançois CambienDavid-alexandre TrégouëtMaurizia GrassoSteven McginnUwe VölkerThomas MeitingerThomas MeitingerStefan WeissL. Duboscq-bidotL. Duboscq-bidotRichard DorentVera Regitz-zagrosekFolkert W. AsselbergsFolkert W. AsselbergsHélène BlanchéOlivier DubourgPatrick LacolleyPierre BoutouyrieDelphine Bacq-daianVincent FontaineVincent FontaineVolker RuppertMarine GermainK LehnertJean-noël TrochuStuart A. CookStuart A. CookAngélique CurjolBrendan J. KeatingIbticem RajiAnne BolandJ. ErdmannMichael MorleyJean-françois AupetitPaloma RemiorLuigi TavazziGérard RoizèsMichal MokryKonstantin StrauchKonstantin StrauchRichard IsnardRichard IsnardJean-philippe EmpanaRobert OlasoKenneth B. MarguilesZofia T. BilińskaStephan B. FelixMarcus DörrThomas P. CappolaBlankenberg StefanJan HaasCéline BesseJean-françois DeleuzeChristine E. SeidmanChristine E. SeidmanChristian HengstenbergChristian HengstenbergJessica Van SettenHakon HakonarsonSanjay K PrasadDaiane HemerichPascal De GrooteThomas WichterAlain Van MilMichel KomajdaMichel KomajdaRenee MaasCarole ProustDeclan P. O'reganXavier JouvenGanapathi Varma SaripellaGanapathi Varma SaripellaGeorgios KararigasEloisa ArbustiniJin LiKlaus StarkLaurent FauchierFlavie AderFlavie AderMelanie WaldenbergerMartina Müller-nurasyidEric VillardEric VillardSophie GarnierSophie Garniersubject
Cardiac & Cardiovascular SystemsCardiomyopathy Dilated/genetics[SDV]Life Sciences [q-bio]Signal Transducing/geneticsDilated cardiomyopathyGenome-wide association studyAdaptor Proteins Signal Transducing/genetics030204 cardiovascular system & hematologyTAURINE0302 clinical medicineGWASMedicinePOSITION STATEMENT1102 Cardiorespiratory Medicine and HaematologyGenetics0303 health scienceseducation.field_of_studyGenetic Predisposition to Disease/geneticsAdaptor ProteinsDilated cardiomyopathy4C-sequencingPolymorphism Single Nucleotide/geneticsGenetic risk scoreCardiology and Cardiovascular MedicineLife Sciences & BiomedicineSingle Nucleotide/geneticsCardiomyopathy DilatedCardiomyopathyPopulationLocus (genetics)Single-nucleotide polymorphismPolymorphism Single NucleotideChromosomes03 medical and health sciencesSystolic/geneticsHeart Failure Systolic/geneticsSNPAnimalsHumansGenetic Predisposition to DiseaseAllelePolymorphismeducationImputationAdaptor Proteins Signal Transducing030304 developmental biologyHeart FailureScience & Technologybusiness.industryWORKING GROUP1103 Clinical Sciencesmedicine.diseaseGenetic architectureCardiovascular System & Hematology Dilated cardiomyopathyDilated/geneticsCardiovascular System & Cardiology[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologiebusinessApoptosis Regulatory ProteinsHeart Failure SystolicGenome-Wide Association Studydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-03-03 |