Large-scale Genome-wide Analysis Identifies Genetic Variants Associated with Cardiac Structure and Function

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.

Citing Articles

Molecular convergence of risk variants for congenital heart defects leveraging a regulatory map of the human fetal heart.

Ma X, Conley S, Kosicki M, Bredikhin D, Cui R, Tran S medRxiv. 2024; .

PMID: 39606363 PMC: 11601760. DOI: 10.1101/2024.11.20.24317557.

Dilated Cardiomyopathy: A Genetic Journey from Past to Future.

Newman N, Burke M Int J Mol Sci. 2024; 25(21).

PMID: 39519012 PMC: 11546582. DOI: 10.3390/ijms252111460.

Atrial cardiomyopathy revisited-evolution of a concept: a clinical consensus statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and the Latin American....

Goette A, Corradi D, Dobrev D, Aguinaga L, Cabrera J, Chugh S Europace. 2024; 26(9).

PMID: 39077825 PMC: 11431804. DOI: 10.1093/europace/euae204.

Deep learning of left atrial structure and function provides link to atrial fibrillation risk.

Pirruccello J, Di Achille P, Choi S, Ramo J, Khurshid S, Nekoui M Nat Commun. 2024; 15(1):4304.

PMID: 38773065 PMC: 11109224. DOI: 10.1038/s41467-024-48229-w.

Association of rs35006907 Polymorphism with Risk of Dilated Cardiomyopathy in Han Chinese Population.

Yang C, Chen F, Li S, Zeng X, Wang S, Lan J Balkan J Med Genet. 2024; 26(1):27-34.

PMID: 38711908 PMC: 11071056. DOI: 10.2478/bjmg-2023-0004.

References

Hu B, Copeland N, Gilbert D, Jenkins N, Kilimann M . The paralemmin protein family: identification of paralemmin-2, an isoform differentially spliced to AKAP2/AKAP-KL, and of palmdelphin, a more distant cytosolic relative. Biochem Biophys Res Commun. 2001; 285(5):1369-76. DOI: 10.1006/bbrc.2001.5329. View

Malekar P, Hagenmueller M, Anyanwu A, Buss S, Streit M, Weiss C . Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling. Hypertension. 2010; 55(4):939-45. DOI: 10.1161/HYPERTENSIONAHA.109.141127. View

Sabater-Lleal M, Malarstig A, Folkersen L, Artigas M, Baldassarre D, Kavousi M . Common genetic determinants of lung function, subclinical atherosclerosis and risk of coronary artery disease. PLoS One. 2014; 9(8):e104082. PMC: 4122436. DOI: 10.1371/journal.pone.0104082. View

. A user's guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 2011; 9(4):e1001046. PMC: 3079585. DOI: 10.1371/journal.pbio.1001046. View

Vasan R, Larson M, Aragam J, Wang T, Mitchell G, Kathiresan S . Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study. BMC Med Genet. 2007; 8 Suppl 1:S2. PMC: 1995617. DOI: 10.1186/1471-2350-8-S1-S2. View

Nikpay M, Goel A, Won H, Hall L, Willenborg C, Kanoni S . A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet. 2015; 47(10):1121-1130. PMC: 4589895. DOI: 10.1038/ng.3396. View

Smith N, Felix J, Morrison A, Demissie S, Glazer N, Loehr L . Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. Circ Cardiovasc Genet. 2010; 3(3):256-66. PMC: 3025695. DOI: 10.1161/CIRCGENETICS.109.895763. View

Pers T, Karjalainen J, Chan Y, Westra H, Wood A, Yang J . Biological interpretation of genome-wide association studies using predicted gene functions. Nat Commun. 2015; 6:5890. PMC: 4420238. DOI: 10.1038/ncomms6890. View

Saarikangas J, Mattila P, Varjosalo M, Bovellan M, Hakanen J, Calzada-Wack J . Missing-in-metastasis MIM/MTSS1 promotes actin assembly at intercellular junctions and is required for integrity of kidney epithelia. J Cell Sci. 2011; 124(Pt 8):1245-55. DOI: 10.1242/jcs.082610. View

10.

Schunkert H, Konig I, Kathiresan S, Reilly M, Assimes T, Holm H . Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet. 2011; 43(4):333-8. PMC: 3119261. DOI: 10.1038/ng.784. View

11.

Bulik-Sullivan B, Loh P, Finucane H, Ripke S, Yang J, Patterson N . LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015; 47(3):291-5. PMC: 4495769. DOI: 10.1038/ng.3211. View

12.

Dunckley T, Huentelman M, Craig D, Pearson J, Szelinger S, Joshipura K . Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med. 2007; 357(8):775-88. DOI: 10.1056/NEJMoa070174. View

13.

Rossin E, Lage K, Raychaudhuri S, Xavier R, Tatar D, Benita Y . Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet. 2011; 7(1):e1001273. PMC: 3020935. DOI: 10.1371/journal.pgen.1001273. View

14.

Vasan R, Larson M, Benjamin E, Evans J, Levy D . Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction. N Engl J Med. 1997; 336(19):1350-5. DOI: 10.1056/NEJM199705083361903. View

15.

Lee D, Pencina M, Benjamin E, Wang T, Levy D, ODonnell C . Association of parental heart failure with risk of heart failure in offspring. N Engl J Med. 2006; 355(2):138-47. DOI: 10.1056/NEJMoa052948. View

16.

Levy D, Ehret G, Rice K, Verwoert G, Launer L, Dehghan A . Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009; 41(6):677-87. PMC: 2998712. DOI: 10.1038/ng.384. View

17.

Oh J, Appleton C, Hatle L, Nishimura R, Seward J, Tajik A . The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 1997; 10(3):246-70. DOI: 10.1016/s0894-7317(97)70062-2. View

18.

Pan S, Nakayama T, Sato N, Izumi Y, Soma M, Aoi N . A haplotype of the GOSR2 gene is associated with myocardial infarction in Japanese men. Genet Test Mol Biomarkers. 2013; 17(6):481-8. PMC: 3668501. DOI: 10.1089/gtmb.2012.0379. View

19.

Willer C, Li Y, Abecasis G . METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010; 26(17):2190-1. PMC: 2922887. DOI: 10.1093/bioinformatics/btq340. View

20.

Skol A, Scott L, Abecasis G, Boehnke M . Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet. 2006; 38(2):209-13. DOI: 10.1038/ng1706. View