Biophysical Reviews

, Volume 7, Issue 1, pp 141–159 | Cite as

Decoding the complex genetic causes of heart diseases using systems biology

  • Djordje Djordjevic
  • Vinita Deshpande
  • Tomasz Szczesnik
  • Andrian Yang
  • David T. Humphreys
  • Eleni Giannoulatou
  • Joshua W. K. HoEmail author


The pace of disease gene discovery is still much slower than expected, even with the use of cost-effective DNA sequencing and genotyping technologies. It is increasingly clear that many inherited heart diseases have a more complex polygenic aetiology than previously thought. Understanding the role of gene–gene interactions, epigenetics, and non-coding regulatory regions is becoming increasingly critical in predicting the functional consequences of genetic mutations identified by genome-wide association studies and whole-genome or exome sequencing. A systems biology approach is now being widely employed to systematically discover genes that are involved in heart diseases in humans or relevant animal models through bioinformatics. The overarching premise is that the integration of high-quality causal gene regulatory networks (GRNs), genomics, epigenomics, transcriptomics and other genome-wide data will greatly accelerate the discovery of the complex genetic causes of congenital and complex heart diseases. This review summarises state-of-the-art genomic and bioinformatics techniques that are used in accelerating the pace of disease gene discovery in heart diseases. Accompanying this review, we provide an interactive web-resource for systems biology analysis of mammalian heart development and diseases, CardiacCode ( CardiacCode features a dataset of over 700 pieces of manually curated genetic or molecular perturbation data, which enables the inference of a cardiac-specific GRN of 280 regulatory relationships between 33 regulator genes and 129 target genes. We believe this growing resource will fill an urgent unmet need to fully realise the true potential of predictive and personalised genomic medicine in tackling human heart disease.


Cardiac gene regulatory network Whole-genome sequencing Epigenomics Congenital heart disease Cardiomyopathy Gene prioritisation 


Compliance with ethical standards


This study was supported by the Victor Chang Cardiac Research Institute, and a grant by the Human Frontier Science Program (RGY0084/2014).

Conflict of interest

All authors (D.D., V.D., T.S., A.Y., D.T.H., E.G., and J.W.K.H.) declare that they do not have any conflict of interest.

Ethical approval

This article does not contain any studies with human or animal subjects performed by any of the authors.

Supplementary material

12551_2014_145_MOESM1_ESM.xls (369 kb)
ESM 1 (XLS 369 kb)


  1. Alekseyenko AA, Ho JWK, Peng S, Gelbart M, Tolstorukov MY, Plachetka A, Kharchenko PV, Jung YL, Gorchakov AA, Larschan E et al (2012) Sequence-specific targeting of dosage compensation in drosophila favors an active chromatin context. PLoS Genet 8:e1002646PubMedCentralPubMedGoogle Scholar
  2. Alvarez-Saavedra M, Carrasco L, Sura-Trueba S, Demarchi Aiello V, Walz K, Neto JX, Young JI (2010) Elevated expression of MeCP2 in cardiac and skeletal tissues is detrimental for normal development. Hum Mol Genet 19:2177–2190PubMedGoogle Scholar
  3. Azuaje F, Zhang L, Jeanty C, Puhl S-L, Rodius S, Wagner DR (2013) Analysis of a gene co-expression network establishes robust association between Col5a2 and ischemic heart disease. BMC Med Genomics 6:13PubMedCentralPubMedGoogle Scholar
  4. Ballouz S, Liu JY, George RA, Bains N, Liu A, Oti M, Gaeta B, Fatkin D, Wouters MA (2013) Gentrepid V2.0: a web server for candidate disease gene prediction. BMC Bioinformatics 14:249PubMedCentralPubMedGoogle Scholar
  5. Ballouz S, Liu JY, Oti M, Gaeta B, Fatkin D, Bahlo M, Wouters MA (2014) Candidate disease gene prediction using gentrepid: application to a genome-wide association study on coronary artery disease. Mol Genet Genomic Med 2:44–57PubMedCentralPubMedGoogle Scholar
  6. Barabasi A-L, Gulbahce N, Loscalzo J (2011) Network medicine: a network-based approach to human disease. Nat Rev Genet 12:56–68PubMedCentralPubMedGoogle Scholar
  7. Barriot R, Breckpot J, Thienpont B, Brohée S, Van Vooren S, Coessens B, Tranchevent L-C, Van Loo P, Gewillig M, Devriendt K et al (2010) Collaboratively charting the gene-to-phenotype network of human congenital heart defects. Genome Med 2:16PubMedCentralPubMedGoogle Scholar
  8. Barth AS, Merk S, Arnoldi E, Zwermann L, Kloos P, Gebauer M, Steinmeyer K, Bleich M, Kääb S, Hinterseer M, Kartmann H, Kreuzer E, Dugas M, Steinbeck G, Nabauer M (2005) Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature. Circ Res 96:1022–1029PubMedGoogle Scholar
  9. Beckmann JS, Estivill X, Antonarakis SE (2007) Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nat Rev Genet 8:639–646PubMedGoogle Scholar
  10. Berger SI, Ma’ayan A, Iyengar R (2010) Systems pharmacology of arrhythmias. Sci Signal 3:ra30Google Scholar
  11. Bernabeu Llinares MO (2011) An open source HPC-enabled model of cardiac defibrillation of the human heart. Doctoral dissertation, Oxford UniversityGoogle Scholar
  12. Blow MJ, McCulley DJ, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F et al (2010) ChIP-Seq identification of weakly conserved heart enhancers. Nat Genet 42:806–810PubMedCentralPubMedGoogle Scholar
  13. Blue GM, Kirk EP, Sholler GF, Harvey RP, Winlaw DS (2012) Congenital heart disease: current knowledge about causes and inheritance. Med J Aust 197:155–159PubMedGoogle Scholar
  14. Breckpot J, Thienpont B, Bauters M, Tranchevent L-C, Gewillig M, Allegaert K, Vermeesch JR, Moreau Y, Devriendt K (2012) Congenital heart defects in a novel recurrent 22q11.2 deletion harboring the genes CRKL and MAPK1. Am J Med Genet A 158A:574–580PubMedGoogle Scholar
  15. Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5:877–889PubMedGoogle Scholar
  16. Callis TE, Pandya K, Seok HY, Tang R-H, Tatsuguchi M, Huang Z-P, Chen J-F, Deng Z, Gunn B, Shumate J et al (2009) MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest 119:2772–2786PubMedCentralPubMedGoogle Scholar
  17. Cappola TP, Li M, He J, Ky B, Gilmore J, Qu L, Keating B, Reilly M, Kim CE, Glessner J et al (2010) Common variants in HSPB7 and FRMD4B associated with advanced heart failure. Circ Cardiovasc Genet 3:147–154PubMedCentralPubMedGoogle Scholar
  18. Chamberlain AA, Lin M, Lister RL, Maslov AA, Wang Y, Suzuki M, Wu B, Greally JM, Zheng D, Zhou B (2014) DNA methylation is developmentally regulated for genes essential for cardiogenesis. J Am Heart Assoc 3:e000976PubMedCentralPubMedGoogle Scholar
  19. Chang S, McKinsey TA, Zhang CL, Richardson JA, Hill JA, Olson EN (2004) Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol 24:8467–8476PubMedCentralPubMedGoogle Scholar
  20. Chatr-aryamontri A, Breitkreutz B-J, Heinicke S, Boucher L, Winter A, Stark C, Nixon J, Ramage L, Kolas N, O_Donnell L et al (2012) The BioGRID interaction database: 2013 update. Nucleic Acids Res 41:D816–D823PubMedCentralPubMedGoogle Scholar
  21. Chen H, VanBuren V (2014) A provisional gene regulatory atlas for mouse heart development. PLoS ONE 9:e83364PubMedCentralPubMedGoogle Scholar
  22. Chen Y-H, Xu S-J, Bendahhou S, Wang X-L, Wang Y, Xu W-Y, Jin H-W, Sun H, Su X-Y, Zhuang Q-N et al (2003) KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 299:251–254PubMedGoogle Scholar
  23. Chen J-F, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL, Wang D-Z (2006) The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 38:228–233PubMedCentralPubMedGoogle Scholar
  24. Chowdhury S, Erickson SW, MacLeod SL, Cleves MA, Hu P, Karim MA, Hobbs CA (2011) Maternal genome-wide DNA methylation patterns and congenital heart defects. PLoS ONE 6:e16506PubMedCentralPubMedGoogle Scholar
  25. Cirulli ET, Goldstein DB (2010) Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 11:415–425PubMedGoogle Scholar
  26. Claussnitzer M, Dankel SN, Klocke B, Grallert H, Glunk V, Berulava T, Lee H, Oskolkov N, Fadista J, Ehlers K et al (2014) Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms. Cell 156:343–358PubMedGoogle Scholar
  27. Csardi G, Nepusz T (2006) The igraph software package for complex network research. InterJournal Complex Systems 1695Google Scholar
  28. Da Costa Martins PA, Bourajjaj M, Gladka M, Kortland M, van Oort RJ, Pinto YM, Molkentin JD, De Windt LJ (2008) Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling. Circulation 118:1567–1576PubMedGoogle Scholar
  29. De Jong AM, Maass AH, Oberdorf-Maass SU, Van Veldhuisen DJ, Van Gilst WH, Van Gelder IC (2010) Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation. Cardiovasc Res 89:754–765Google Scholar
  30. De la Pompa JL, Epstein JA (2012) Coordinating tissue interactions: notch signaling in cardiac development and disease. Dev Cell 22:244–254PubMedCentralPubMedGoogle Scholar
  31. Deb A (2014) Cell-cell interaction in the heart via Wnt/β-catenin pathway after cardiac injury. Cardiovasc Res 102:214–223PubMedGoogle Scholar
  32. Delgado-Olguin P, Huang Y, Li X, Christodoulou D, Seidman CE, Seidman JG, Tarakhovsky A, Bruneau BG (2012) Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet 44:343–347PubMedCentralPubMedGoogle Scholar
  33. Deo R, Albert CM (2012) Epidemiology and genetics of sudden cardiac death. Circulation 125:620–637PubMedCentralPubMedGoogle Scholar
  34. Dewey FE, Perez MV, Wheeler MT, Watt C, Spin J, Langfelder P, Horvath S, Hannenhalli S, Cappola TP, Ashley EA (2011) Gene coexpression network topology of cardiac development, hypertrophy, and failure. Circ Cardiovasc Genet 4:26–35PubMedCentralPubMedGoogle Scholar
  35. Dickel DE, Zhu Y, Nord AS, Wylie JN, Akiyama JA, Afzal V, Plajzer-Frick I, Kirkpatrick A, Göttgens B, Bruneau BG et al (2014) Function-based identification of mammalian enhancers using site-specific integration. Nat Methods 11:566–571PubMedCentralPubMedGoogle Scholar
  36. Dickerson JE, Zhu A, Robertson DL, Hentges KE (2011) Defining the role of essential genes in human disease. PLoS ONE 6:e27368PubMedCentralPubMedGoogle Scholar
  37. Ehrenberg M (2003) Systems biology is taking off. Genome Res 13:2377–2380PubMedGoogle Scholar
  38. Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11:446–450PubMedCentralPubMedGoogle Scholar
  39. Ernst J, Kellis M (2012) ChromHMM: automating chromatin-state discovery and characterization. Nat Methods 9:215–216PubMedCentralPubMedGoogle Scholar
  40. Erwin GD, Oksenberg N, Truty RM, Kostka D, Murphy KK, Ahituv N, Pollard KS, Capra JA (2014) Integrating diverse datasets improves developmental enhancer prediction. PLoS Comput Biol 10:e1003677PubMedCentralPubMedGoogle Scholar
  41. Fahed AC, Gelb BD, Seidman JG, Seidman CE (2013) Genetics of congenital heart disease: the glass half empty. Circ Res 112:707–720PubMedGoogle Scholar
  42. Fakhro KA, Choi M, Ware SM, Belmont JW, Towbin JA, Lifton RP, Khokha MK, Brueckner M (2011) Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. Proc Natl Acad Sci USA 108:2915–2920PubMedCentralPubMedGoogle Scholar
  43. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, Lin J, Minguez P, Bork P, von Mering C et al (2012) STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 41:D808–D815PubMedCentralPubMedGoogle Scholar
  44. Gelb BD, Chung WK (2014) Complex genetics and the etiology of human congenital heart disease. Cold Spring Harb Perspect Med 4:a013953Google Scholar
  45. Glukhov AV, Fedorov VV, Kalish PW, Ravikumar VK, Lou Q, Janks D, Schuessler RB, Moazami N, Efimov IR (2012) Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy. Circulation 125:1835–1847PubMedCentralPubMedGoogle Scholar
  46. Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabasi AL (2007) The human disease network. Proc Natl Acad Sci USA 104:8685–8690PubMedCentralPubMedGoogle Scholar
  47. Greenway SC, Pereira AC, Lin JC, DePalma SR, Israel SJ, Mesquita SM, Ergul E, Conta JH, Korn JM, McCarroll SA et al (2009) De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet 41:931–935PubMedCentralPubMedGoogle Scholar
  48. Grote P, Wittler L, Hendrix D, Koch F, Währisch S, Beisaw A, Macura K, Bläss G, Kellis M, Werber M et al (2013) The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell 24:206–214PubMedCentralPubMedGoogle Scholar
  49. Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, Walters GB, Thorgeirsson G, Gulcher J, Mathiesen EB, Njølstad I, Nyrnes A et al (2009) A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 41:876–878PubMedCentralPubMedGoogle Scholar
  50. Gusterson RJ, Jazrawi E, Adcock IM, Latchman DS (2003) The transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity. J Biol Chem 278:6838–6847PubMedGoogle Scholar
  51. Han P, Hang CT, Yang J, Chang C-P (2011) Chromatin remodeling in cardiovascular development and physiology. Circ Res 108:378–396PubMedCentralPubMedGoogle Scholar
  52. Hang CT, Yang J, Han P, Cheng H-L, Shang C, Ashley E, Zhou B, Chang C-P (2010) Chromatin regulation by Brg1 underlies heart muscle development and disease. Nature 466:62–67PubMedCentralPubMedGoogle Scholar
  53. He A, Kong SW, Ma Q, Pu WT (2011) Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart. Proc Natl Acad Sci U S A 108:5632–5637PubMedCentralPubMedGoogle Scholar
  54. He A, Ma Q, Cao J, von Gise A, Zhou P, Xie H, Zhang B, Hsing M, Christodoulou DC, Cahan P et al (2012) Polycomb repressive complex 2 regulates normal development of the mouse heart. Circ Res 110:406–415PubMedCentralPubMedGoogle Scholar
  55. Hershberger RE, Hedges DJ, Morales A (2013) Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 10:531–547PubMedGoogle Scholar
  56. Ho JWK, Stefani M, dos Remedios CG, Charleston MA (2008) Differential variability analysis of gene expression and its application to human diseases. Bioinformatics 24:i390–i398PubMedCentralPubMedGoogle Scholar
  57. Ho JWK, Jung YL, Liu T, Alver BH, Lee S, Ikegami K, Sohn K-A, Minoda A, Tolstorukov MY, Appert A et al (2014) Comparative analysis of metazoan chromatin organization. Nature 512:449–452PubMedCentralPubMedGoogle Scholar
  58. Hookana E (2012) Characteristics of victims of non-ischemic sudden cardiac death. Doctoral dissertation, University of OuluGoogle Scholar
  59. Ideker T, Galitski T, Hood L (2001) A new approach to decoding life: systems biology. Annu Rev Genomics Hum Genet 2:343–372PubMedGoogle Scholar
  60. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–821PubMedGoogle Scholar
  61. Junion G, Spivakov M, Girardot C, Braun M, Gustafson EH, Birney E, Furlong EEM (2012) A transcription factor collective defines cardiac cell fate and reflects lineage history. Cell 148:473–486PubMedGoogle Scholar
  62. Kacprowski T, Doncheva NT, Albrecht M (2013) NetworkPrioritizer: a versatile tool for network-based prioritization of candidate disease genes or other molecules. Bioinformatics 29:1471–1473PubMedCentralPubMedGoogle Scholar
  63. Kamisago M, Sharma SD, DePalma SR, Solomon S, Sharma P, McDonough B, Smoot L, Mullen MP, Woolf PK, Wigle ED, Seidman JG, Seidman CE (2000) Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 343:1688–1696PubMedGoogle Scholar
  64. Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M (2013) Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res 42:D199–D205PubMedCentralPubMedGoogle Scholar
  65. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M (1991) Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 252:704–706PubMedGoogle Scholar
  66. Kelder T, van Iersel MP, Hanspers K, Kutmon M, Conklin BR, Evelo CT, Pico AR (2011) WikiPathways: building research communities on biological pathways. Nucleic Acids Res 40:D1301–D1307PubMedCentralPubMedGoogle Scholar
  67. Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T et al (1997) Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 16:379–382PubMedGoogle Scholar
  68. Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S et al (2013) Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 152:570–583PubMedCentralPubMedGoogle Scholar
  69. Kohler S, Bauer S, Horn D, Robinson PN (2008) Walking the interactome for prioritization of candidate disease genes. Am J Hum Genet 82:949–958PubMedCentralPubMedGoogle Scholar
  70. Krajinovic M, Pinamonti B, Sinagra G, Vatta M, Severini GM, Milasin J, Falaschi A, Camerini F, Giacca M, Mestroni L (1995) Linkage of familial dilated cardiomyopathy to chromosome 9. Heart muscle disease study group. Am J Hum Genet 57:846–852PubMedCentralPubMedGoogle Scholar
  71. Krauthammer M, Kaufmann CA, Gilliam TC, Rzhetsky A (2004) Molecular triangulation: bridging linkage and molecular-network information for identifying candidate genes in Alzheimer’s disease. Proc Natl Acad Sci USA 101:15148–15153PubMedCentralPubMedGoogle Scholar
  72. Lachke SA, Ho JWK, Kryukov GV, O’Connell DJ, Aboukhalil A, Bulyk ML, Park PJ, Maas RL (2012) ISyTE: integrated systems tool for Eye gene discovery. Invest Ophthalmol Vis Sci 53:1617–1627PubMedCentralPubMedGoogle Scholar
  73. Lage K, Møllgard K, Greenway S, Wakimoto H, Gorham JM, Workman CT, Bendsen E, Hansen NT, Rigina O, Roque FS, et al. (2010) Dissecting spatio-temporal protein networks driving human heart development and related disorders. Mol Syst Biol 6:381Google Scholar
  74. Lage K, Greenway SC, Rosenfeld JA, Wakimoto H, Gorham JM, Segrè AV, Roberts AE, Smoot LB, Pu WT, Pereira AC et al (2012) Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development. Proc Natl Acad Sci U S A 109:14035–14040PubMedCentralPubMedGoogle Scholar
  75. Li W, Chen L, He W, Li W, Qu X, Liang B, Gao Q, Feng C, Jia X, Lv Y et al (2013) Prioritizing disease candidate proteins in cardiomyopathy-specific protein-protein interaction networks based on “guilt by association? analysis. PLoS ONE 8:e71191PubMedCentralPubMedGoogle Scholar
  76. Li X, Martinez-Fernandez A, Hartjes KA, Kocher J-PA, Olson TM, Terzic A, Nelson TJ (2014) Transcriptional atlas of cardiogenesis maps congenital heart disease interactome. Physiol Genomics 46:482–495PubMedGoogle Scholar
  77. Lin Q, Schwarz J, Bucana C, Olson EN (1997) Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276:1404–1407PubMedGoogle Scholar
  78. Lin C-C, Hsiang J-T, Wu C-Y, Oyang Y-J, Juan H-F, Huang H-C (2010) Dynamic functional modules in co-expressed protein interaction networks of dilated cardiomyopathy. BMC Syst Biol 4:138PubMedCentralPubMedGoogle Scholar
  79. Liu N, Bezprozvannaya S, Williams AH, Qi X, Richardson JA, Bassel-Duby R, Olson EN (2008) microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev 22:3242–3254PubMedCentralPubMedGoogle Scholar
  80. Lokody I (2014) Genetic therapies: correcting genetic defects with CRISPR-Cas9. Nat Rev Genet 15:63PubMedGoogle Scholar
  81. Lyons I, Parsons LM, Hartley L, Li R, Andrews JE, Robb L, Harvey RP (1995) Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev 9:1654–1666PubMedGoogle Scholar
  82. MacLellan WR, Wang Y, Lusis AJ (2012) Systems-based approaches to cardiovascular disease. Nat Rev Cardiol 9:172–184PubMedGoogle Scholar
  83. MacRae CA (2010) The genetics of congestive heart failure. Heart Fail Clin 6:223–230PubMedCentralPubMedGoogle Scholar
  84. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A et al (2009) Finding the missing heritability of complex diseases. Nature 461:747–753PubMedCentralPubMedGoogle Scholar
  85. Mar JC, Matigian NA, Mackay-Sim A, Mellick GD, Sue CM, Silburn PA, McGrath JJ, Quackenbush J, Wells CA (2011) Variance of gene expression identifies altered network constraints in neurological disease. PLoS Genet 7:e1002207PubMedCentralPubMedGoogle Scholar
  86. Matkovich SJ, Van Booven DJ, Eschenbacher WH, Dorn GW 2nd (2011) RISC RNA sequencing for context-specific identification of in vivo microRNA targets. Circ Res 108:18–26PubMedCentralPubMedGoogle Scholar
  87. Matkovich SJ, Edwards JR, Grossenheider TC, de Guzman Strong C, Dorn GW 2nd (2014) Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs. Proc Natl Acad Sci USA 111:12264–12269PubMedGoogle Scholar
  88. May D, Blow MJ, Kaplan T, McCulley DJ, Jensen BC, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C et al (2012) Large-scale discovery of enhancers from human heart tissue. Nat Genet 44:89–93Google Scholar
  89. McCulley DJ, Black BL (2012) Transcription factor pathways and congenital heart disease. Curr Top Dev Biol 100:253–277PubMedCentralPubMedGoogle Scholar
  90. Merlo M, Pyxaras SA, Pinamonti B, Barbati G, Di Lenarda A, Sinagra G (2011) Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment. J Am Coll Cardiol 57:1468–1476PubMedGoogle Scholar
  91. Messina DN, Speer MC, Pericak-Vance MA, McNally EM (1997) Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23. Am J Hum Genet 61:909–917PubMedCentralPubMedGoogle Scholar
  92. Miyamoto S, Kawamura T, Morimoto T, Ono K, Wada H, Kawase Y, Matsumori A, Nishio R, Kita T, Hasegawa K (2006) Histone acetyltransferase activity of p300 is required for the promotion of left ventricular remodeling after myocardial infarction in adult mice in vivo. Circulation 113:679–690PubMedGoogle Scholar
  93. Molkentin JD, Lin Q, Duncan SA, Olson EN (1997) Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev 11:1061–1072PubMedGoogle Scholar
  94. Montgomery RL, Potthoff MJ, Haberland M, Qi X, Matsuzaki S, Humphries KM, Richardson JA, Bassel-Duby R, Olson EN (2008) Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J Clin Invest 118:3588–3597PubMedCentralPubMedGoogle Scholar
  95. Myerburg RJ (2001) Sudden cardiac death: exploring the limits of our knowledge. J Cardiovasc Electrophysiol 12:369–381PubMedGoogle Scholar
  96. Myocardial Infarction Genetics Consortium, Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC et al. (2009) Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 41:334–341PubMedGoogle Scholar
  97. Narlikar L, Sakabe NJ, Blanski AA, Arimura FE, Westlund JM, Nobrega MA, Ovcharenko I (2010) Genome-wide discovery of human heart enhancers. Genome Res 20:381–392PubMedCentralPubMedGoogle Scholar
  98. Padmanabhan N, Jia D, Geary-Joo C, Wu X, Ferguson-Smith AC, Fung E, Bieda MC, Snyder FF, Gravel RA, Cross JC et al (2013) Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155:81–93PubMedGoogle Scholar
  99. Padovan-Merhar O, Raj A (2013) Using variability in gene expression as a tool for studying gene regulation. Rev Syst Biol Med 5:751–759Google Scholar
  100. Papait R, Cattaneo P, Kunderfranco P, Greco C, Carullo P, Guffanti A, Viganò V, Stirparo GG, Latronico MVG, Hasenfuss G et al (2013) Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy. Proc Natl Acad Sci U S A 110:20164–20169PubMedCentralPubMedGoogle Scholar
  101. Park A, Won ST, Pentecost M, Bartkowski W, Lee B (2014) CRISPR/Cas9 allows efficient and complete knock-in of a destabilization domain-tagged essential protein in a human cell line, allowing rapid knockdown of protein function. PLoS ONE 9:e95101PubMedCentralPubMedGoogle Scholar
  102. Patterson AJ, Chen M, Xue Q, Xiao D, Zhang L (2010) Chronic prenatal hypoxia induces epigenetic programming of PKCepsilon gene repression in rat hearts. Circ Res 107:365–373PubMedCentralPubMedGoogle Scholar
  103. Pauling L, Itano HA (1949) Sickle cell anemia a molecular disease. Science 110:543–548PubMedGoogle Scholar
  104. Peterkin T, Gibson A, Patient R (2003) GATA-6 maintains BMP-4 and Nkx2 expression during cardiomyocyte precursor maturation. EMBO J 22:4260–4273PubMedCentralPubMedGoogle Scholar
  105. Ran FA, Hsu PD, Lin C-Y, Gootenberg JS, Konermann S, Trevino AE, Scott DA, Inoue A, Matoba S, Zhang Y et al (2013) Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154:1380–1389PubMedGoogle Scholar
  106. Roach JC, Glusman G, Smit AFA, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M et al (2010) Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328:636–639PubMedCentralPubMedGoogle Scholar
  107. Runyan RB, Markwald RR (1983) Invasion of mesenchyme into three-dimensional collagen gels: a regional and temporal analysis of interaction in embryonic heart tissue. Dev Biol 95:108–114PubMedGoogle Scholar
  108. Sadrieh A, Domanski L, Pitt-Francis J, Mann SA, Hodkinson EC, Ng CA, Perry MD, Taylor JA, Gavaghan D, Subbiah RN, Vandenberg JI, Hill AP (2014) Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2. Nat Commun 5:5069PubMedGoogle Scholar
  109. Sanchez-Castro M, Gordon CT, Petit F, Nord AS, Callier P, Andrieux J, Guérin P, Pichon O, David A, Abadie V et al (2013) Congenital heart defects in patients with deletions upstream of SOX9. Hum Mutat 34:1628–1631PubMedGoogle Scholar
  110. Savu O, Jurcuţ R, Giuşcă S, van Mieghem T, Gussi I, Popescu BA, Ginghină C, Rademakers F, Deprest J, Voigt JU (2012) Circ Cardiovasc Imaging 5:289–297PubMedGoogle Scholar
  111. Saxena A, Tabin CJ (2010) miRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation. Proc Natl Acad Sci U S A 107:87–91PubMedCentralPubMedGoogle Scholar
  112. Schlesinger, J., Schueler, M., Grunert, M., Fischer, J.J., Zhang, Q., Krueger, T., Lange, M., Tönjes, M., Dunkel, I., and Sperling, S.R. (2011). The cardiac transcription network modulated by Gata4, Mef2a, Nkx2.5, Srf, histone modifications, and microRNAs. PLoS Genet 7, e1001313.Google Scholar
  113. Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA, Mikkelsen TS, Heckl D, Ebert BL, Root DE, Doench JG et al (2014) Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343:84–87PubMedCentralPubMedGoogle Scholar
  114. Sheng W, Qian Y, Zhang P, Wu Y, Wang H, Ma X, Chen L, Ma D, Huang G (2014) Association of promoter methylation statuses of congenital heart defect candidate genes with tetralogy of fallot. J Transl Med 12:31PubMedCentralPubMedGoogle Scholar
  115. Sherwood RI, Hashimoto T, O’Donnell CW, Lewis S, Barkal AA, van Hoff JP, Karun V, Jaakkola T, Gifford DK (2014) Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape. Nat Biotechnol 32:171–178PubMedCentralPubMedGoogle Scholar
  116. Smaill BH, Hunter PJ (2010) Computer modeling of electrical activation: from cellular dynamics to the whole heart. In: Sigg DC, Iaizzo PA, Xiao Y-F, He B (eds)_Cardiac electrophysiology methods and models. Springer, New York, pp 159–185Google Scholar
  117. Smemo S, Campos LC, Moskowitz IP, Krieger JE, Pereira AC, Nobrega MA (2012) Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Hum Mol Genet 21:3255–3263PubMedCentralPubMedGoogle Scholar
  118. Smith RP, Taher L, Patwardhan RP, Kim MJ, Inoue F, Shendure J, Ovcharenko I, Ahituv N (2013) Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model. Nat Genet 45:1021–1028PubMedCentralPubMedGoogle Scholar
  119. Soemedi R, Wilson IJ, Bentham J, Darlay R, Töpf A, Zelenika D, Cosgrove C, Setchfield K, Thornborough C, Granados-Riveron J et al (2012) Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. Am J Hum Genet 91:489–501PubMedCentralPubMedGoogle Scholar
  120. Song J, Chen KC (2014) Spectacle: faster and more accurate chromatin state annotation using spectral learning. Cold Spring Harbor Laboratory, Cold Spring HarborGoogle Scholar
  121. Sperling SR (2011) Systems biology approaches to heart development and congenital heart disease. Cardiovasc Res 91:269–278PubMedGoogle Scholar
  122. Stennard FA, Costa MW, Lai D, Biben C, Furtado MB, Solloway MJ, McCulley DJ, Leimena C, Preis JI, Dunwoodie SL, Elliott DE, Prall OW, Black BL, Fatkin D, Harvey RP (2005) Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation. Development 132:2451–2462PubMedGoogle Scholar
  123. Strasser BJ (1999) Perspectives: molecular medicine. “Sickle cell anemia, a molecular disease”. Science 286:1488–1490PubMedGoogle Scholar
  124. Takeuchi JK, Lou X, Alexander JM, Sugizaki H, Delgado-Olguín P, Holloway AK, Mori AD, Wylie JN, Munson C, Zhu Y et al (2011) Chromatin remodelling complex dosage modulates transcription factor function in heart development. Nat Commun 2:187PubMedCentralPubMedGoogle Scholar
  125. Tan N, Chung MK, Smith JD, Hsu J, Serre D, Newton DW, Castel L, Soltesz E, Pettersson G, Gillinov AM et al (2013) Weighted gene coexpression network analysis of human left atrial tissue identifies gene modules associated with atrial fibrillation. Circ Cardiovasc Genet 6:362–371PubMedCentralPubMedGoogle Scholar
  126. Tanaka M, Chen Z, Bartunkova S, Yamasaki N, Izumo S (1999) The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development 126:1269–1280PubMedGoogle Scholar
  127. Tester DJ, Medeiros-Domingo A, Will ML, Haglund CM, Ackerman MJ (2012) Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. Mayo Clin Proc 87:524–539PubMedCentralPubMedGoogle Scholar
  128. Thienpont B, Zhang L, Postma AV, Breckpot J, Tranchevent L-C, Van Loo P, Møllgård K, Tommerup N, Bache I, Tümer Z, van Engelen K, Menten B, Mortier G, Waggoner D, Gewillig M, Moreau Y, Devriendt K, Larsen LA (2010) Haploinsufficiency of TAB2 causes congenital heart defects in humans. Am J Hum Genet 86:839–849PubMedCentralPubMedGoogle Scholar
  129. Tranchevent L-C, Barriot R, Yu S, Van Vooren S, Van Loo P, Coessens B, De Moor B, Aerts S, Moreau Y (2008) ENDEAVOUR update: a web resource for gene prioritization in multiple species. Nucleic Acids Res 36:W377–W384PubMedCentralPubMedGoogle Scholar
  130. Tranchevent L-C, Capdevila FB, Nitsch D, De Moor B, De Causmaecker P, Moreau Y (2010) A guide to web tools to prioritize candidate genes. Brief Bioinform 12:22–32PubMedGoogle Scholar
  131. Trapnell C, Cacchiarelli D, Grimsby J, Pokharel P, Li S, Morse M, Lennon NJ, Livak KJ, Mikkelsen TS, Rinn JL (2014) The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol 32:381–386PubMedCentralPubMedGoogle Scholar
  132. Trent RJ (2012) Molecular and cellular therapies. Elsevier, AmsterdamGoogle Scholar
  133. Udali S, Guarini P, Moruzzi S, Choi S-W, Friso S (2013) Cardiovascular epigenetics: from DNA methylation to microRNAs. Mol Asp Med 34:883–901Google Scholar
  134. Van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN (2007) Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316:575–579PubMedGoogle Scholar
  135. Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, Jaenisch R (2013a) One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153:910–918PubMedCentralPubMedGoogle Scholar
  136. Wang VY, Hoogendoorn C, Frangi AF, Cowan BR, Hunter PJ, Young AA, Nash MP (2013) Automated personalised human left ventricular FE models to investigate heart failure mechanics. Proceedings of the third international conference on Statistical Atlases and Computational Models of the Heart: imaging and modelling challenges; 10/2012, pp 307–316Google Scholar
  137. Wang T, Wei JJ, Sabatini DM, Lander ES (2014) Genetic screens in human cells using the CRISPR-Cas9 system. Science 343:80–84PubMedCentralPubMedGoogle Scholar
  138. Wellcome Trust Case Control Consortium, Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S, Vukcevic D, Barnes C, Conrad DF et al (2010) Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464:713–720PubMedGoogle Scholar
  139. Westerhoff HV, Palsson BO (2004) The evolution of molecular biology into systems biology. Nat Biotechnol 22:1249–1252PubMedGoogle Scholar
  140. White MA, Myers CA, Corbo JC, Cohen BA (2013) Massively parallel in vivo enhancer assay reveals that highly local features determine the cis-regulatory function of ChIP-seq peaks. Proc Natl Acad Sci U S A 110:11952–11957PubMedCentralPubMedGoogle Scholar
  141. Wills QF, Livak KJ, Tipping AJ, Enver T, Goldson AJ, Sexton DW, Holmes C (2013) Single-cell gene expression analysis reveals genetic associations masked in whole-tissue experiments. Nat Biotechnol 31:748–752PubMedGoogle Scholar
  142. Wu Y, Liang D, Wang Y, Bai M, Tang W, Bao S, Yan Z, Li D, Li J (2013) Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell Stem Cell 13:659–662PubMedGoogle Scholar
  143. Xie C, Yuan J, Li H, Li M, Zhao G, Bu D, Zhu W, Wu W, Chen R, Zhao Y (2014) NONCODEv4: exploring the world of long non-coding RNA genes. Nucleic Acids Res 42:D98–103PubMedCentralPubMedGoogle Scholar
  144. Xu H, Morishima M, Wylie JN, Schwartz RJ, Bruneau BG, Lindsay EA, Baldini A (2004) Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development 131:3217–3227PubMedGoogle Scholar
  145. Xu M, Wu X, Li Y, Yang X, Hu J, Zheng M, Tian J (2014) CITED2 mutation and methylation in children with congenital heart disease. J Biomed Sci 21:7PubMedCentralPubMedGoogle Scholar
  146. Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, Romano-Adesman A, Bjornson RD, Breitbart RE, Brown KK et al (2013) De novo mutations in histone-modifying genes in congenital heart disease. Nature 498:220–223PubMedCentralPubMedGoogle Scholar
  147. Zhang Q-J, Chen H-Z, Wang L, Liu D-P, Hill JA, Liu Z-P (2011) The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J Clin Invest 121:2447–2456PubMedCentralPubMedGoogle Scholar
  148. Zhang J, Ma X, Wang H, Ma D, Huang G (2014) Elevated methylation of the RXRA promoter region may be responsible for its downregulated expression in the myocardium of patients with TOF. Pediatr Res 75:588–594PubMedGoogle Scholar
  149. Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303–317PubMedGoogle Scholar

Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Djordje Djordjevic
    • 1
    • 2
  • Vinita Deshpande
    • 1
  • Tomasz Szczesnik
    • 1
    • 2
  • Andrian Yang
    • 1
  • David T. Humphreys
    • 1
    • 2
  • Eleni Giannoulatou
    • 1
    • 2
  • Joshua W. K. Ho
    • 1
    • 2
    Email author
  1. 1.Victor Chang Cardiac Research InstituteDarlinghurstAustralia
  2. 2.St. Vincent’s Clinical SchoolThe University of New South WalesDarlinghurstAustralia

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