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Clinical Trial
. 2017 May 1;127(5):1798-1812.
doi: 10.1172/JCI84840. Epub 2017 Apr 10.

Large-scale Genome-Wide Analysis Identifies Genetic Variants Associated With Cardiac Structure and Function

Philipp S WildJanine F FelixArne SchillertAlexander TeumerMing-Huei ChenMaarten J G LeeningUwe VölkerVera GroßmannJennifer A BrodyMarguerite R IrvinSanjiv J ShahSetia PramanaWolfgang LiebReinhold SchmidtAlice V StantonDörthe MalzahnAlbert Vernon SmithJohan SundströmCosetta MinelliDaniela RuggieroLeo-Pekka LyytikäinenDaniel TillerJ Gustav SmithClaire MonnereauMarco R Di TullioSolomon K MusaniAlanna C MorrisonTune H PersMichael MorleyMarcus E KleberJayashri AragamEmelia J BenjaminJoshua C BisEgbert BispingUlrich BroeckelSusan ChengJaap W DeckersFabiola Del Greco MFrank EdelmannMyriam FornageLude FrankeNele FriedrichTamara B HarrisEdith HoferAlbert HofmanJie HuangAlun D HughesMika KähönenKnhi InvestigatorsJochen KruppaKarl J LacknerLars LannfeltRafael LaskowskiLenore J LaunerMargrét LeosdottirHonghuang LinCecilia M LindgrenChristina LoleyCalum A MacRaeDeborah MascalzoniJamil MayetDaniel MedenwaldAndrew P MorrisChristian MüllerMartina Müller-NurasyidStefania NappoPeter M NilssonSebastian NudingTeresa NutileAnnette PetersArne PfeuferDiana PietznerPeter P PramstallerOlli T RaitakariKenneth M RiceFernando RivadeneiraJerome I RotterSaku T RuohonenRalph L SaccoTandaw E SamdarshiHelena SchmidtAndrew S P SharpDenis C ShieldsRossella SoriceNona SotoodehniaBruno H StrickerPraveen SurendranSimon ThomAnna M TöglhoferAndré G UitterlindenRolf WachterHenry VölzkeAndreas ZieglerThomas MünzelWinfried MärzThomas P CappolaJoel N HirschhornGary F MitchellNicholas L SmithErvin R FoxNicole D DuekerVincent W V JaddoeOlle MelanderMartin RussTerho LehtimäkiMarina CiulloAndrew A HicksLars LindVilmundur GudnasonBurkert PieskeAnthony J BarronRobert ZweikerHeribert SchunkertErik IngelssonKiang LiuDonna K ArnettBruce M PsatyStefan BlankenbergMartin G LarsonStephan B FelixOscar H FrancoTanja ZellerRamachandran S VasanMarcus Dörr
Free PMC article
Clinical Trial

Large-scale Genome-Wide Analysis Identifies Genetic Variants Associated With Cardiac Structure and Function

Philipp S Wild et al. J Clin Invest. .
Free PMC article

Abstract

Background: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.

Methods: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.

Results: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.

Conclusion: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

Funding: For detailed information per study, see Acknowledgments.

Conflict of interest statement

Conflict of interest: Author conflicts of interest are listed in the supplemental material.

Figures

Figure 1
Figure 1. Flowchart of the analytical 3-stage approach.
*For LV systolic dysfunction as binary trait, the selection criterion for the MAF was ≥0.03. Acronyms of cohorts are explained in the supplemental material. Mv-E (E), peak velocity of early diastolic transmitral inflow; Mv-A (A), peak velocity of transmitral inflow corresponding to atrial contraction; E/A, ratio of mitral E- and A-wave; DecTime, deceleration time of mitral E-wave; IVRT, isovolumetric relaxation time; E′, peak velocity of excursion of lateral mitral annulus in early diastolic phase; E/E′, ratio of E and E′; DDpEF, diastolic dysfunction with preserved ejection fraction; HFpEF, HF with preserved ejection fraction; LVM, LV mass; LVDD, LV diastolic dimension; LA, left atrium; FS, LV fractional shortening; LVSD, LV systolic dysfunction; MAF, minor allele frequency; Ncohorts, number of cohorts included in analysis; Nsubjects, number of subjects investigated per phenotype; LD, linkage disequilibrium; CAD, coronary artery disease; oevar_imp., observed divided by expected variance for imputed allele dosage. Vasan et al. JAMA 2009 is ref. .
Figure 2
Figure 2. Manhattan plots of echocardiographic phenotypes with genome-wide findings in the joint analysis of discovery and replication cohorts.
The plots show the SNP-wise log P values against their genomic position for (A) aortic root diameter (AoD), (B) LV diastolic dimension (LVDD), and (C) peak velocity of the transmitral inflow corresponding to the atrial contraction (Mv-A). The genome-wide significant loci and the gene nearest to the top SNP are highlighted in yellow if they were discovered in the present analysis and in blue if they had been identified in the earlier analysis. The horizontal gray lines indicate the significance threshold of P = 5 × 10–8. P values were obtained by calculating Wald test statistics. The number of samples (n) per trait is reported in the upper left corner of each panel.
Figure 3
Figure 3. Forest plot for the meta-analysis of the association between rs6702619 and AoD, with the corresponding regional plot including functional annotation.
P values were obtained by calculating Wald test statistics using a sample size of n = 26,741. Total sample size in the forest plot is n = 30,704.
Figure 4
Figure 4. Forest plot for the meta-analysis of the association between rs12541595 and LVDD, with the corresponding regional plot including functional annotation.
P values were obtained by calculating Wald test statistics using a sample size of n = 30,201. Total sample size in the forest plot is n = 43,623.
Figure 5
Figure 5. Forest plot for the meta-analysis of the association between rs12440869 and Mv-A, with the corresponding regional plot including functional annotation.
P values were obtained by calculating Wald test statistics using a sample size of n = 21,156. Total sample size in the forest plot is n = 36,430.

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