Induced Pluripotent Stem Cells in Disease Modeling and Gene Identification

  • Satish Kumar
  • John Blangero
  • Joanne E. Curran
Part of the Methods in Molecular Biology book series (MIMB, volume 1706)


Experimental modeling of human inherited disorders provides insight into the cellular and molecular mechanisms involved, and the underlying genetic component influencing, the disease phenotype. The breakthrough development of induced pluripotent stem cell (iPSC) technology represents a quantum leap in experimental modeling of human diseases, providing investigators with a self-renewing and, thus, unlimited source of pluripotent cells for targeted differentiation. In principle, the entire range of cell types found in the human body can be interrogated using an iPSC approach. Therefore, iPSC technology, and the increasingly refined abilities to differentiate iPSCs into disease-relevant target cells, has far-reaching implications for understanding disease pathophysiology, identifying disease-causing genes, and developing more precise therapeutics, including advances in regenerative medicine. In this chapter, we discuss the technological perspectives and recent developments in the application of patient-derived iPSC lines for human disease modeling and disease gene identification.

Key words

Cellular reprogramming iPSC Human complex disease Genetics 


  1. 1.
    Lander ES (2011) Initial impact of the sequencing of the human genome. Nature 470(7333):187–197. PubMedCrossRefGoogle Scholar
  2. 2.
    Handley A, Schauer T, Ladurner AG et al (2015) Designing cell-type-specific genome-wide experiments. Mol Cell 58(4):621–631. PubMedCrossRefGoogle Scholar
  3. 3.
    Phillips KA, Bales KL, Capitanio JP et al (2014) Why primate models matter. Am J Primatol 76(9):801–827. PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Seok J, Warren HS, Cuenca AG et al (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 110(9):3507–3512. PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Springer MS, Murphy WJ, Eizirik E et al (2003) Placental mammal diversification and the cretaceous-tertiary boundary. Proc Natl Acad Sci U S A 100(3):1056–1061. PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Masters JR, Stacey GN (2007) Changing medium and passaging cell lines. Nat Protoc 2(9):2276–2284PubMedCrossRefGoogle Scholar
  7. 7.
    Min JL, Barrett A, Watts T et al (2010) Variability of gene expression profiles in human blood and lymphoblastoid cell lines. BMC Genomics 11:96. PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Caliskan M, Cusanovich DA, Ober C et al (2011) The effects of EBV transformation on gene expression levels and methylation profiles. Hum Mol Genet 20(8):1643–1652. PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Nestor CE, Ottaviano R, Reinhardt D et al (2015) Rapid reprogramming of epigenetic and transcriptional profiles in mammalian culture systems. Genome Biol 16:11. PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Horvath P, Aulner N, Bickle M et al (2016) Screening out irrelevant cell-based models of disease. Nat Rev Drug Discov 15(11):751–769. PubMedCrossRefGoogle Scholar
  11. 11.
    Avior Y, Sagi I, Benvenisty N (2016) Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol 17(3):170–182. PubMedCrossRefGoogle Scholar
  12. 12.
    Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292(5819):154–156PubMedCrossRefGoogle Scholar
  13. 13.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147PubMedCrossRefGoogle Scholar
  14. 14.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676PubMedCrossRefGoogle Scholar
  15. 15.
    Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872PubMedCrossRefGoogle Scholar
  16. 16.
    Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920PubMedCrossRefGoogle Scholar
  17. 17.
    Park IH, Zhao R, West JA et al (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451(7175):141–146PubMedCrossRefGoogle Scholar
  18. 18.
    Aasen T, Raya A, Barrero MJ et al (2008) Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26(11):1276–1284. PubMedCrossRefGoogle Scholar
  19. 19.
    Hanna J, Markoulaki S, Schorderet P et al (2008) Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133(2):250–264. PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Utikal J, Maherali N, Kulalert W et al (2009) Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell Sci 122(Pt 19):3502–3510. PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Carette JE, Pruszak J, Varadarajan M et al (2010) Generation of iPSCs from cultured human malignant cells. Blood 115(20):4039–4042. PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Miyoshi N, Ishii H, Nagai K et al (2010) Defined factors induce reprogramming of gastrointestinal cancer cells. Proc Natl Acad Sci U S A 107(1):40–45. PubMedCrossRefGoogle Scholar
  23. 23.
    Seki T, Yuasa S, Oda M et al (2010) Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7(1):11–14. PubMedCrossRefGoogle Scholar
  24. 24.
    Tsai SY, Clavel C, Kim S et al (2010) Oct4 and klf4 reprogram dermal papilla cells into induced pluripotent stem cells. Stem Cells 28(2):221–228. PubMedGoogle Scholar
  25. 25.
    Kim J, Lengner CJ, Kirak O et al (2011) Reprogramming of postnatal neurons into induced pluripotent stem cells by defined factors. Stem Cells 29(6):992–1000. PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kumar S, Curran JE, Glahn DC et al (2016) Utility of lymphoblastoid cell lines for induced pluripotent stem cell generation. Stem Cells Int 2016:2349261. PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Rubin LL (2008) Stem cells and drug discovery: the beginning of a new era? Cell 132(4):549–552. PubMedCrossRefGoogle Scholar
  28. 28.
    Maehr R, Chen S, Snitow M et al (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A 106(37):15768–15773. PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Chun YS, Chaudhari P, Jang YY (2010) Applications of patient-specific induced pluripotent stem cells; focused on disease modeling, drug screening and therapeutic potentials for liver disease. Int J Biol Sci 6(7):796–805PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Ghodsizadeh A, Taei A, Totonchi M et al (2010) Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev 6(4):622–632. PubMedCrossRefGoogle Scholar
  31. 31.
    Rashid ST, Corbineau S, Hannan N et al (2010) Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest 120(9):3127–3136. PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Rosenzweig A (2010) Illuminating the potential of pluripotent stem cells. N Engl J Med 363(15):1471–1472. PubMedCrossRefGoogle Scholar
  33. 33.
    Yoshida Y, Yamanaka S (2010) Recent stem cell advances: induced pluripotent stem cells for disease modeling and stem cell-based regeneration. Circulation 122(1):80–87. PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang N, An MC, Montoro D et al (2010) Characterization of human Huntington’s disease cell model from induced pluripotent stem cells. PLoS Curr 2:RRN1193. PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Brennand KJ, Simone A, Jou J et al (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473(7346):221–225. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Kondo T, Asai M, Tsukita K et al (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12(4):487–496. PubMedCrossRefGoogle Scholar
  37. 37.
    Liang P, Du J (2014) Human induced pluripotent stem cell for modeling cardiovascular diseases. Regen Med Res 2(1):4. PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Brennand K, Savas JN, Kim Y et al (2015) Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 20(3):361–368. PubMedCrossRefGoogle Scholar
  39. 39.
    NIMH-RGR Data Explorer (2015) NIMH Repository and Genomics Resource, USA. Accessed 14 Oct 2015
  40. 40.
    Okita K, Yamakawa T, Matsumura Y et al (2013) An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells 31(3):458–466. PubMedCrossRefGoogle Scholar
  41. 41.
    Rajesh D, Dickerson SJ, Yu J et al (2011) Human lymphoblastoid B-cell lines reprogrammed to EBV-free induced pluripotent stem cells. Blood 118(7):1797–1800. PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Choi SM, Liu H, Chaudhari P et al (2011) Reprogramming of EBV-immortalized B-lymphocyte cell lines into induced pluripotent stem cells. Blood 118(7):1801–1805. PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Roe T, Reynolds TC, Yu G et al (1993) Integration of murine leukemia virus DNA depends on mitosis. EMBO J 12(5):2099–2108PubMedPubMedCentralGoogle Scholar
  44. 44.
    Bukrinsky MI, Sharova N, Dempsey MP et al (1992) Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc Natl Acad Sci U S A 89(14):6580–6584PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Medvedev SP, Shevchenko AI, Zakian SM (2010) Induced pluripotent stem cells: problems and advantages when applying them in regenerative medicine. Acta Nat 2(2):18–28Google Scholar
  46. 46.
    Rao MS, Malik N (2012) Assessing iPSC reprogramming methods for their suitability in translational medicine. J Cell Biochem 113(10):3061–3068. PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Chang CW, Lai YS, Pawlik KM et al (2009) Polycistronic lentiviral vector for “hit and run” reprogramming of adult skin fibroblasts to induced pluripotent stem cells. Stem Cells 27(5):1042–1049. PubMedCrossRefGoogle Scholar
  48. 48.
    Soldner F, Hockemeyer D, Beard C et al (2009) Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136(5):964–977. PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Sommer CA, Stadtfeld M, Murphy GJ et al (2009) Induced pluripotent stem cell generation using a single lentiviral stem cell cassette. Stem Cells 27(3):543–549. PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Somers A, Jean JC, Sommer CA et al (2010) Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells 28(10):1728–1740. PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    KUROYA M, ISHIDA N (1953) Newborn virus pneumonitis (type Sendai). II. The isolation of a new virus possessing hemagglutinin activity. Yokohama Med Bull 4(4):217–233PubMedGoogle Scholar
  52. 52.
    Fusaki N, Ban H, Nishiyama A et al (2009) Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 85(8):348–362PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Ban H, Nishishita N, Fusaki N et al (2011) Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proc Natl Acad Sci U S A 108(34):14234–14239. PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Schlaeger TM, Daheron L, Brickler TR et al (2015) A comparison of non-integrating reprogramming methods. Nat Biotechnol 33(1):58–63. PubMedCrossRefGoogle Scholar
  55. 55.
    Sun TQ, Fenstermacher DA, Vos JM (1994) Human artificial episomal chromosomes for cloning large DNA fragments in human cells. Nat Genet 8(1):33–41. PubMedCrossRefGoogle Scholar
  56. 56.
    Simpson K, McGuigan A, Huxley C (1996) Stable episomal maintenance of yeast artificial chromosomes in human cells. Mol Cell Biol 16(9):5117–5126PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Westphal EM, Sierakowska H, Livanos E et al (1998) A system for shuttling 200-kb BAC/PAC clones into human cells: stable extrachromosomal persistence and long-term ectopic gene activation. Hum Gene Ther 9(13):1863–1873. PubMedCrossRefGoogle Scholar
  58. 58.
    Yu J, Hu K, Smuga-Otto K et al (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324(5928):797–801. PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hu K, Yu J, Suknuntha K et al (2011) Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood 117(14):e109–e119. PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Lin T, Ambasudhan R, Yuan X et al (2009) A chemical platform for improved induction of human iPSCs. Nat Methods 6(11):805–808. PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Yu J, Chau KF, Vodyanik MA et al (2011) Efficient feeder-free episomal reprogramming with small molecules. PLoS One 6(3):e17557. PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Chou BK, Mali P, Huang X et al (2011) Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. Cell Res 21(3):518–529. PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Okita K, Matsumura Y, Sato Y et al (2011) A more efficient method to generate integration-free human iPS cells. Nat Methods 8(5):409–412. PubMedCrossRefGoogle Scholar
  64. 64.
    Warren L, Manos PD, Ahfeldt T et al (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7(5):618–630. PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Goh PA, Caxaria S, Casper C et al (2013) A systematic evaluation of integration free reprogramming methods for deriving clinically relevant patient specific induced pluripotent stem (iPS) cells. PLoS One 8(11):e81622. PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Warren L, Ni Y, Wang J et al (2012) Feeder-free derivation of human induced pluripotent stem cells with messenger RNA. Sci Rep 2:657. PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Merkle FT, Eggan K (2013) Modeling human disease with pluripotent stem cells: from genome association to function. Cell Stem Cell 12(6):656–668. PubMedCrossRefGoogle Scholar
  68. 68.
    Kajiwara M, Aoi T, Okita K et al (2012) Donor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells. Proc Natl Acad Sci U S A 109(31):12538–12543. PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Mills JA, Wang K, Paluru P et al (2013) Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines. Blood 122(12):2047–2051. PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Shao K, Koch C, Gupta MK et al (2013) Induced pluripotent mesenchymal stromal cell clones retain donor-derived differences in DNA methylation profiles. Mol Ther 21(1):240–250. PubMedCrossRefGoogle Scholar
  71. 71.
    Rouhani F, Kumasaka N, de Brito MC et al (2014) Genetic background drives transcriptional variation in human induced pluripotent stem cells. PLoS Genet 10(6):e1004432. PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kyttala A, Moraghebi R, Valensisi C et al (2016) Genetic variability overrides the impact of parental cell type and determines iPSC differentiation potential. Stem Cell Rep 6(2):200–212. CrossRefGoogle Scholar
  73. 73.
    Bock C, Kiskinis E, Verstappen G et al (2011) Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144(3):439–452. PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Boulting GL, Kiskinis E, Croft GF et al (2011) A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol 29(3):279–286. PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    HD iPSC Consortium (2012) Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11(2):264–278. CrossRefGoogle Scholar
  76. 76.
    Cohen DE, Melton D (2011) Turning straw into gold: directing cell fate for regenerative medicine. Nat Rev Genet 12(4):243–252. PubMedCrossRefGoogle Scholar
  77. 77.
    Williams LA, Davis-Dusenbery BN, Eggan KC (2012) SnapShot: directed differentiation of pluripotent stem cells. Cell 149(5):1174–1174.e1. PubMedCrossRefGoogle Scholar
  78. 78.
    Lian X, Zhang J, Azarin SM et al (2013) Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta-catenin signaling under fully defined conditions. Nat Protoc 8(1):162–175. PubMedCrossRefGoogle Scholar
  79. 79.
    Yan Y, Shin S, Jha BS et al (2013) Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells. Stem Cells Transl Med 2(11):862–870. PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Carlson C, Koonce C, Aoyama N et al (2013) Phenotypic screening with human iPS cell-derived cardiomyocytes: HTS-compatible assays for interrogating cardiac hypertrophy. J Biomol Screen 18(10):1203–1211. PubMedCrossRefGoogle Scholar
  81. 81.
    Drawnel FM, Boccardo S, Prummer M et al (2014) Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells. Cell Rep 9(3):810–821. PubMedCrossRefGoogle Scholar
  82. 82.
    Slukvin II, Vodyanik MA, Thomson JA et al (2006) Directed differentiation of human embryonic stem cells into functional dendritic cells through the myeloid pathway. J Immunol 176(5):2924–2932PubMedCrossRefGoogle Scholar
  83. 83.
    Erceg S, Lainez S, Ronaghi M et al (2008) Differentiation of human embryonic stem cells to regional specific neural precursors in chemically defined medium conditions. PLoS One 3(5):e2122. PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Prigodich AE, Seferos DS, Massich MD et al (2009) Nano-flares for mRNA regulation and detection. ACS Nano 3(8):2147–2152. PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Larsson HM, Lee ST, Roccio M et al (2012) Sorting live stem cells based on Sox2 mRNA expression. PLoS One 7(11):e49874. PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Tohyama S, Hattori F, Sano M et al (2013) Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 12(1):127–137. PubMedCrossRefGoogle Scholar
  87. 87.
    Nguyen HN, Byers B, Cord B et al (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8(3):267–280. PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Israel MA, Yuan SH, Bardy C et al (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482(7384):216–220. PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Reinhardt P, Schmid B, Burbulla LF et al (2013) Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12(3):354–367. PubMedCrossRefGoogle Scholar
  90. 90.
    Ieda M, JD F, Delgado-Olguin P et al (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142(3):375–386. PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Szabo E, Rampalli S, Risueno RM et al (2010) Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468(7323):521–526. PubMedCrossRefGoogle Scholar
  92. 92.
    Vierbuchen T, Ostermeier A, Pang ZP et al (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041. PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Sekiya S, Suzuki A (2011) Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475(7356):390–393. PubMedCrossRefGoogle Scholar
  94. 94.
    Ring KL, Tong LM, Balestra ME et al (2012) Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell 11(1):100–109. PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Vierbuchen T, Wernig M (2011) Direct lineage conversions: unnatural but useful? Nat Biotechnol 29(10):892–907. PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Yang C, Al-Aama J, Stojkovic M et al (2015) Concise review: cardiac disease modeling using induced pluripotent stem cells. Stem Cells 33(9):2643–2651. PubMedCrossRefGoogle Scholar
  97. 97.
    Nishi M, Akutsu H, Kudoh A et al (2014) Induced cancer stem-like cells as a model for biological screening and discovery of agents targeting phenotypic traits of cancer stem cell. Oncotarget 5(18):8665–8680PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Curry EL, Moad M, Robson CN et al (2015) Using induced pluripotent stem cells as a tool for modelling carcinogenesis. World J Stem Cells 7(2):461–469. PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Wiley LA, Burnight ER, Songstad AE et al (2015) Patient-specific induced pluripotent stem cells (iPSCs) for the study and treatment of retinal degenerative diseases. Prog Retin Eye Res 44:15–35. PubMedCrossRefGoogle Scholar
  100. 100.
    Zheng A, Li Y, Tsang SH (2015) Personalized therapeutic strategies for patients with retinitis pigmentosa. Expert Opin Biol Ther 15(3):391–402. PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Lysy PA, Weir GC, Bonner-Weir S (2012) Concise review: pancreas regeneration: recent advances and perspectives. Stem Cells Transl Med 1(2):150–159. PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Abdelalim EM, Bonnefond A, Bennaceur-Griscelli A et al (2014) Pluripotent stem cells as a potential tool for disease modelling and cell therapy in diabetes. Stem Cell Rev 10(3):327–337. PubMedCrossRefGoogle Scholar
  103. 103.
    Peitz M, Jungverdorben J, Brustle O (2013) Disease-specific iPS cell models in neuroscience. Curr Mol Med 13(5):832–841PubMedCrossRefGoogle Scholar
  104. 104.
    Crook JM, Wallace G, Tomaskovic-Crook E (2015) The potential of induced pluripotent stem cells in models of neurological disorders: implications on future therapy. Expert Rev Neurother 15(3):295–304. PubMedCrossRefGoogle Scholar
  105. 105.
    Goring HH, Curran JE, Johnson MP et al (2007) Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat Genet 39(10):1208–1216. PubMedCrossRefGoogle Scholar
  106. 106.
    Winnier DA, Fourcaudot M, Norton L et al (2015) Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). PLoS One 10(4):e0119941. PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Pasca SP, Portmann T, Voineagu I et al (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17(12):1657–1662. PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Prilutsky D, Palmer NP, Smedemark-Margulies N et al (2014) iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls. Trends Mol Med 20(2):91–104. PubMedCrossRefGoogle Scholar
  109. 109.
    Wen Z, Nguyen HN, Guo Z et al (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515(7527):414–418. PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Farra N, Zhang WB, Pasceri P et al (2012) Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations. Mol Psychiatry 17(12):1261–1271. PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Vaccarino FM, Urban AE, Stevens HE et al (2011) Annual research review: the promise of stem cell research for neuropsychiatric disorders. J Child Psychol Psychiatry 52(4):504–516. PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Vaccarino FM, Stevens HE, Kocabas A et al (2011) Induced pluripotent stem cells: a new tool to confront the challenge of neuropsychiatric disorders. Neuropharmacology 60(7-8):1355–1363. PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Stevens HE, Mariani J, Coppola G et al (2012) Neurobiology meets genomic science: the promise of human-induced pluripotent stem cells. Dev Psychopathol 24(4):1443–1451. PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Chae JI, Kim DW, Lee N et al (2012) Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington’s disease patient. Biochem J 446(3):359–371. PubMedCrossRefGoogle Scholar
  115. 115.
    Szlachcic WJ, Switonski PM, Krzyzosiak WJ et al (2015) Huntington disease iPSCs show early molecular changes in intracellular signaling, the expression of oxidative stress proteins and the p53 pathway. Dis Model Mech 8(9):1047–1057. PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44(7):660–669PubMedCrossRefGoogle Scholar
  117. 117.
    White T, Anjum A, Schulz SC (2006) The schizophrenia prodrome. Am J Psychiatry 163(3):376–380PubMedCrossRefGoogle Scholar
  118. 118.
    Gulsuner S, Walsh T, Watts AC et al (2013) Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154(3):518–529. PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Mariani J, Simonini MV, Palejev D et al (2012) Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Natl Acad Sci U S A 109(31):12770–12775. PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Nicholas CR, Chen J, Tang Y et al (2013) Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12(5):573–586. PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Espuny-Camacho I, Michelsen KA, Gall D et al (2013) Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77(3):440–456. PubMedCrossRefGoogle Scholar
  122. 122.
    Maroof AM, Keros S, Tyson JA et al (2013) Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12(5):559–572. PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Hu BY, Du ZW, Zhang SC (2009) Differentiation of human oligodendrocytes from pluripotent stem cells. Nat Protoc 4(11):1614–1622. PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Wang S, Bates J, Li X et al (2013) Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12(2):252–264. PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Kim C, Wong J, Wen J et al (2013) Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature 494(7435):105–110. PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Maher B (2008) Personal genomes: the case of the missing heritability. Nature 456(7218):18–21. PubMedCrossRefGoogle Scholar
  127. 127.
    Manolio TA, Collins FS, Cox NJ et al (2009) Finding the missing heritability of complex diseases. Nature 461(7265):747–753.; 10.1038/nature08494
  128. 128.
    Franke A, McGovern DP, Barrett JC et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42(12):1118–1125. PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Cardno AG, Gottesman II (2000) Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 97(1):12–17.;2-U[pii]
  130. 130.
    Sullivan PF, Kendler KS, Neale MC (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 60(12):1187–1192. PubMedCrossRefGoogle Scholar
  131. 131.
    Visscher PM, Goddard ME, Derks EM et al (2012) Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses. Mol Psychiatry 17(5):474–485. PubMedCrossRefGoogle Scholar
  132. 132.
    McGuire SE, McGuire AL (2008) Don’t throw the baby out with the bathwater: enabling a bottom-up approach in genome-wide association studies. Genome Res 18(11):1683–1685. PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Tracy RP (2008) ‘Deep phenotyping’: characterizing populations in the era of genomics and systems biology. Curr Opin Lipidol 19(2):151–157. PubMedCrossRefGoogle Scholar
  134. 134.
    Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408(6810):307–310. PubMedCrossRefGoogle Scholar
  135. 135.
    Chao EC, Lipkin SM (2006) Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis. Nucleic Acids Res 34(3):840–852PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Goh KI, Cusick ME, Valle D et al (2007) The human disease network. Proc Natl Acad Sci U S A 104(21):8685–8690PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Lage K, Hansen NT, Karlberg EO et al (2008) A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes. Proc Natl Acad Sci U S A 105(52):20870–20875. PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Barshir R, Shwartz O, Smoly IY et al (2014) Comparative analysis of human tissue interactomes reveals factors leading to tissue-specific manifestation of hereditary diseases. PLoS Comput Biol 10(6):e1003632. PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Jenkinson CP, Goring HH, Arya R et al (2015) Transcriptomics in type 2 diabetes: bridging the gap between genotype and phenotype. Genom Data 8:25–36. PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Kim H, Kim JS (2014) A guide to genome engineering with programmable nucleases. Nat Rev Genet 15(5):321–334. PubMedCrossRefGoogle Scholar
  141. 141.
    Boch J, Scholze H, Schornack S et al (2009) Breaking the code of DNA binding specificity of TAL-type III effectors. Science 326(5959):1509–1512. PubMedCrossRefGoogle Scholar
  142. 142.
    Wood AJ, Lo TW, Zeitler B et al (2011) Targeted genome editing across species using ZFNs and TALENs. Science 333(6040):307. PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Sanjana NE, Cong L, Zhou Y et al (2012) A transcription activator-like effector toolbox for genome engineering. Nat Protoc 7(1):171–192. PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Cong L, Ran FA, Cox D et al (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121):819–823. PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Mali P, Yang L, Esvelt KM et al (2013) RNA-guided human genome engineering via Cas9. Science 339(6121):823–826. PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Carroll D, Morton JJ, Beumer KJ et al (2006) Design, construction and in vitro testing of zinc finger nucleases. Nat Protoc 1(3):1329–1341PubMedCrossRefGoogle Scholar
  147. 147.
    Miller JC, Tan S, Qiao G et al (2011) A TALE nuclease architecture for efficient genome editing. Nat Biotechnol 29(2):143–148. PubMedCrossRefGoogle Scholar
  148. 148.
    Jinek M, Chylinski K, Fonfara I et al (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–821. PubMedCrossRefGoogle Scholar
  149. 149.
    Musunuru K (2013) Genome editing of human pluripotent stem cells to generate human cellular disease models. Dis Model Mech 6(4):896–904. PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Lombardo A, Genovese P, Beausejour CM et al (2007) Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat Biotechnol 25(11):1298–1306PubMedCrossRefGoogle Scholar
  151. 151.
    Suzuki K, Mitsui K, Aizawa E et al (2008) Highly efficient transient gene expression and gene targeting in primate embryonic stem cells with helper-dependent adenoviral vectors. Proc Natl Acad Sci U S A 105(37):13781–13786. PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Zou J, Maeder ML, Mali P et al (2009) Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell 5(1):97–110. PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Hockemeyer D, Wang H, Kiani S et al (2011) Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol 29(8):731–734. PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Li M, Suzuki K, Qu J et al (2011) Efficient correction of hemoglobinopathy-causing mutations by homologous recombination in integration-free patient iPSCs. Cell Res 21(12):1740–1744. PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Sebastiano V, Maeder ML, Angstman JF et al (2011) In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases. Stem Cells 29(11):1717–1726. PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Soldner F, Laganiere J, Cheng AW et al (2011) Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146(2):318–331. PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Yusa K, Rashid ST, Strick-Marchand H et al (2011) Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478(7369):391–394. PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Zou J, Mali P, Huang X et al (2011) Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood 118(17):4599–4608. PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Lan F, Lee AS, Liang P et al (2013) Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell 12(1):101–113. PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  • Satish Kumar
    • 1
  • John Blangero
    • 1
  • Joanne E. Curran
    • 1
  1. 1.South Texas Diabetes and Obesity InstituteUniversity of Texas Rio Grande Valley, School of MedicineEdinburgUSA

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