Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders

Frontiers in Pharmacology

Volumn 5, Issue DEC, 2014, Pages

  Schadt, Eric E ^a   Buchanan, Sean ^b   Brennand, Kristen J ^a   Merchant, Kalpana M ^b,c  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b ELI LILLY AND COMPANY   (United States)

^c TransThera Consulting Co   (United States)

Author keywords

Complex disease mechanism; Drug discovery screening; High throughput biology; Stem cell based screening; Systems biology and network biology

Indexed keywords

BETA CATENIN; BITOPERTIN; CRIZOTINIB; DABRAFENIB; ERLOTINIB; FORETINIB; GEFITINIB; IMATINIB; IMIPRAMINE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; OLAPARIB; POMAGLUMETAD METHIONIL; PROMETHAZINE; RETINOIC ACID; ROSCOVITINE; SONIC HEDGEHOG PROTEIN; TOPIRAMATE; TRAMETINIB; TRASTUZUMAB; VANDETANIB; VEMURAFENIB; WNT PROTEIN;

ALK GENE; ALZHEIMER DISEASE; ANTINEOPLASTIC ACTIVITY; ANTIULCER ACTIVITY; AUTOSOMAL DOMINANT DISORDER; BRAF GENE; BRCA2 GENE; CACNA1C GENE; CACNA1L GENE; CANCER INHIBITION; CANCER RESEARCH; CELL DIFFERENTIATION; CELLS BY BODY ANATOMY; CENTRAL NERVOUS SYSTEM DISEASE; CHRONIC MYELOID LEUKEMIA; COLORECTAL CANCER; COPY NUMBER VARIATION; DEMENTIA; DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS; DISEASE COURSE; DRD2 GENE; DRUG EFFICACY; DRUG RESEARCH; DRUG SCREENING; DRUG SENSITIVITY; EML4 GENE; EPIGENETICS; FUSION GENE; GABAERGIC SYSTEM; GENE EXPRESSION; GENE REGULATORY NETWORK; GENETIC ASSOCIATION; GENETIC HETEROGENEITY; GENETIC SUSCEPTIBILITY; GENETICS; GRIN2A GENE; GRM3 GENE; HIGH THROUGHPUT SCREENING; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INFLAMMATORY BOWEL DISEASE; MELANOMA; MINI MENTAL STATE EXAMINATION; MOLECULAR BIOLOGY; MULTISCALE NETWORK; NERVE CELL; NEUROSCIENCE; NON SMALL CELL LUNG CANCER; NONHUMAN; ONCOGENE MYC; ONCOGENE RAS; OUTCOME ASSESSMENT; PATHOGENESIS; PATHOPHYSIOLOGY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPE; PLURIPOTENT STEM CELL; REVIEW; SCHIZOPHRENIA; SEIZURE; SINGLE NUCLEOTIDE POLYMORPHISM; SMALL CELL LUNG CANCER; TIMOTHY SYNDROME; TUMOR SUPPRESSOR GENE;

EID: 84921718446     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2014.00252     Document Type: Review

References (181)

1. Adams, D. H., Kinon, B. J., Baygani, S., Millen, B. A., Velona, I., Kollack-Walker, S., et al. (2013). A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia. BMC Psychiatry 13:143. doi: 10.1186/1471-244X-13-143
2. Adams, D. H., Zhang, L., Millen, B. A., Kinon, B. J., and Gomez, J. C. (2014). Pomaglumetad methionil (LY2140023 monohydrate) and aripiprazole in patients with schizophrenia: a phase 3, multicenter, double-blind comparison. Schizophr. Res. Treatment 2014:758212. doi: 10.1155/2014/758212
3. Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A., Behjati, S., Biankin, A. V., et al. (2013). Signatures of mutational processes in human cancer. Nature 500, 415-421. doi: 10.1038/nature12477
4. Alzheimer's Association, A. S. (2014). Changing the Trajectory of Alzheimer's Disease: A National Imperative. Available at: http://www.alz.org/documents_custom/trajectory.pdf
5. Ambasudhan, R., Talantova, M., Coleman, R., Yuan, X., Zhu, S., Lipton, S. A., et al. (2011). Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9, 113-118. doi: 10.1016/j.stem.2011.07.002
6. Ananiev, G., Williams, E. C., Li, H., and Chang, Q. (2011). Isogenic pairs of wild type and mutant Induced Pluripotent Stem Cell (iPSC) lines from Rett Syndrome patients as in vitro disease model. PLoS ONE 6:e25255. doi: 10.1371/journal.pone.0025255
7. Astsaturov, I., Ratushny, V., Sukhanova, A., Einarson, M. B., Bagnyukova, T., Zhou, Y., et al. (2010). Synthetic lethal screen of an EGFR-centered network to improve targeted therapies. Sci. Signal. 3:ra67. doi: 10.1126/scisignal.2001083
8. Baek, K. H., Zaslavsky, A., Lynch, R. C., Britt, C., Okada, Y., Siarey, R. J., et al. (2009). Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459, 1126-1130. doi: 10.1038/nature08062
9. Bajrami, I., Kigozi, A., Van Weverwijk, A., Brough, R., Frankum, J., Lord, C. J., et al. (2012). Synthetic lethality of PARP and NAMPT inhibition in triple-negative breast cancer cells. EMBO Mol. Med. 4, 1087-1096. doi: 10.1002/emmm.201201250
10. Baoi, J. (2014). Prevalence of autism spectrum disorder among children aged 8 years. MMWR Morb. Mortal. Wkly. Rep. 63, 1-21.
11. Barabasi, A. L., and Oltvai, Z. N. (2004). Network biology: understanding the cell's functional organization. Nat. Rev. Genet. 5, 101-113. doi: 10.1038/nrg1272
12. Barber, L. J., Sandhu, S., Chen, L., Campbell, J., Kozarewa, I., Fenwick, K., et al. (2013). Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J. Pathol. 229, 422-429. doi: 10.1002/path.4140
13. Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., et al. (2012). The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607. doi: 10.1038/nature11003
14. Berman, D. M., Karhadkar, S. S., Hallahan, A. R., Pritchard, J. I., Eberhart, C. G., Watkins, D. N., et al. (2002). Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297, 1559-1561. doi: 10.1126/science.1073733
15. Brennand, K. J., Silvas, J., Kim, Y., Tran, N., Simone, A., Ladran, I., et al. (2014). Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol. Psychiatry doi: 10.1038/mp.2014.22 [Epub ahead of print].
16. Brennand, K. J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., et al. (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221-225. doi: 10.1038/nature09915
17. Bystrykh, L., Weersing, E., Dontje, B., Sutton, S., Pletcher, M. T., Wiltshire, T., et al. (2005). Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics.' Nat. Genet. 37, 225-232. doi: 10.1038/ng1497
18. Cagan, R. (2013). Bench to bedside with fruit flies: an interview with Ross Cagan. Dis. Model. Mech. 6, 567-569. doi: 10.1242/dmm.012443
19. Caiazzo, M., Dell'Anno, M. T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., et al. (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476, 224-227. doi: 10.1038/nature10284
20. Califano, A., Butte, A. J., Friend, S., Ideker, T., and Schadt, E. (2012). Leveraging models of cell regulation and GWAS data in integrative network-based association studies. Nat. Genet. 44, 841-847. doi: 10.1038/ng.2355
21. Cancer Genome Atlas Research Network. (2013). Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43-49. doi: 10.1038/nature12222
22. Cancer Genome Atlas Research Network. (2014). Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202-209. doi: 10.1038/nature13480
23. Cancer Genome Atlas Research Network, Kandoth, C., Schultz, N., Cherniack, A. D., Akbani, R., Liu, Y., et al. (2013a). Integrated genomic characterization of endometrial carcinoma. Nature 497, 67-73. doi: 10.1038/nature12113
24. Cancer Genome Atlas Research Network, Weinstein, J. N., Collisson, E. A., Mills, G. B., Shaw, K. R., Ozenberger, B. A., et al. (2013b). The cancer genome atlas pan-cancer analysis project. Nat. Genet. 45, 1113-1120. doi: 10.1038/ng.2764
25. Chambers, S. M., Fasano, C. A., Papapetrou, E. P., Tomishima, M., Sadelain, M., and Studer, L. (2009). Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275-280. doi: 10.1038/nbt.1529
26. Chanda, S., Marro, S., Wernig, M., and Sudhof, T. C. (2013). Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation. Proc. Natl. Acad. Sci. U.S.A. 110, 16622-16627. doi: 10.1073/pnas.1316240110
27. Chen, Y., Zhu, J., Lum, P. Y., Yang, X., Pinto, S., MacNeil, D. J., et al. (2008). Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429-435. doi: 10.1038/nature06757
28. Cheung, A. Y., Horvath, L. M., Grafodatskaya, D., Pasceri, P., Weksberg, R., Hotta, A., et al. (2011a). Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum. Mol. Genet. 20, 2103-2115. doi: 10.1093/hmg/ddr093
29. Cheung, H. W., Cowley, G. S., Weir, B. A., Boehm, J. S., Rusin, S., Scott, J. A., et al. (2011b). Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer. Proc. Natl. Acad. Sci. U.S.A. 108, 12372-12377. doi: 10.1073/pnas.1109363108
30. Cobleigh, M. A., Vogel, C. L., Tripathy, D., Robert, N. J., Scholl, S., Fehrenbacher, L., et al. (1999). Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 17, 2639-2648.
31. Corcoran, R. B., Ebi, H., Turke, A. B., Coffee, E. M., Nishino, M., Cogdill, A. P., et al. (2012). EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2, 227-235. doi: 10.1158/2159-8290.CD-11-0341
32. Cortes, J. E., Kantarjian, H., Shah, N. P., Bixby, D., Mauro, M. J., Flinn, I., et al. (2012). Ponatinib in refractory Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 367, 2075-2088. doi: 10.1056/NEJMoa1205127
33. Cummings, J. L., Morstorf, T., and Zhong, K. (2014). Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res. Ther. 6, 37. doi: 10.1186/alzrt269
34. Dar, A. C., Das, T. K., Shokat, K. M., and Cagan, R. L. (2012). Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486, 80-84. doi: 10.1038/nature11127
35. Das, T. K., and Cagan, R. L. (2013). A Drosophila approach to thyroid cancer therapeutics. Drug Discov. Today Technol. 10, e65-e71. doi: 10.1016/j.ddtec.2012.09.004
36. Das Thakur, M., and Stuart, D. D. (2013). The evolution of melanoma resistance reveals therapeutic opportunities. Cancer Res. 73, 6106-6110. doi: 10.1158/0008-5472.CAN-13-1633
37. Davare, M. A., Saborowski, A., Eide, C. A., Tognon, C., Smith, R. L., Elferich, J., et al. (2013). Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc. Natl. Acad. Sci. U.S.A. 110, 19519-19524. doi: 10.1073/pnas.1319583110
38. Demetri, G. D., von Mehren, M., Blanke, C. D., Van den Abbeele, A. D., Eisenberg, B., Roberts, P. J., et al. (2002). Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472-480. doi: 10.1056/NEJMoa020461
39. Demjaha, A., Egerton, A., Murray, R. M., Kapur, S., Howes, O. D., Stone, J. M., et al. (2013). Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol. Psychiatry 75, e11-e13. doi: 10.1016/j.biopsych.2013.06.011
40. Dermime, S., Grignani, F., Clerici, M., Nervi, C., Sozzi, G., Talamo, G. P., et al. (1993). Occurrence of resistance to retinoic acid in the acute promyelocytic leukemia cell line NB4 is associated with altered expression of the pml/RAR alpha protein. Blood 82, 1573-1577.
41. Dimos, J. T., Rodolfa, K. T., Niakan, K. K., Weisenthal, L. M., Mitsumoto, H., Chung, W., et al. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221. doi: 10.1126/science.1158799
42. Druker, B. J. (2008). Translation of the Philadelphia chromosome into therapy for CML. Blood 112, 4808-4817. doi: 10.1182/blood-2008-07-077958
43. Dudley, J. T., Sirota, M., Shenoy, M., Pai, R. K., Roedder, S., Chiang, A. P., et al. (2011). Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease. Sci. Transl. Med. 3:96ra76. doi: 10.1126/scitranslmed.3002648
44. Ebert, A. D., Yu, J., Rose, F. F. Jr., Mattis, V. B., Lorson, C. L., Thomson, J. A., et al. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277-280. doi: 10.1038/nature07677
45. Eifert, C., and Powers, R. S. (2012). From cancer genomes to oncogenic drivers, tumour dependencies and therapeutic targets. Nat. Rev. Cancer 12, 572-578. doi: 10.1038/nrc3299
46. Emilsson, V., Thorleifsson, G., Zhang, B., Leonardson, A. S., Zink, F., Zhu, J., et al. (2008). Genetics of gene expression and its effect on disease. Nature 452, 423-428. doi: 10.1038/nature06758
47. Espuny-Camacho, I., Michelsen, K. A., Gall, D., Linaro, D., Hasche, A., Bonnefont, J., et al. (2013). Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77, 440-456. doi: 10.1016/j.neuron.2012.12.011
48. Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N., Johnson, D. A., Richardson, T. B., et al. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917-921. doi: 10.1038/nature03445
49. Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., et al. (2009). Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123-134. doi: 10.1056/NEJMoa0900212
50. Friboulet, L., Li, N., Katayama, R., Lee, C. C., Gainor, J. F., Crystal, A. S., et al. (2014). The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 4, 662-673. doi: 10.1158/2159-8290.CD-13-0846
51. Fromer, M., Pocklington, A., Kavanagh, D., Williams, H., Dwyer, S., Gormley, P., et al. (2014). De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179-184. doi: 10.1038/nature12929
52. Garnett, M. J., Edelman, E. J., Heidorn, S. J., Greenman, C. D., Dastur, A., Lau, K. W., et al. (2012). Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570-575. doi: 10.1038/nature11005
53. Ghazalpour, A., Doss, S., Sheth, S. S., Ingram-Drake, L. A., Schadt, E. E., Lusis, A. J., et al. (2005). Genomic analysis of metabolic pathway gene expression in mice. Genome Biol. 6:R59. doi: 10.1186/gb-2005-6-7-r59
54. Greenawalt, D. M., Dobrin, R., Chudin, E., Hatoum, I. J., Suver, C., Beaulaurier, J., et al. (2011). A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome Res. 21, 1008-1016. doi: 10.1101/gr.112821.110
55. Hall-Jackson, C. A., Eyers, P. A., Cohen, P., Goedert, M., Boyle, F. T., Hewitt, N., et al. (1999). Paradoxical activation of Raf by a novel Raf inhibitor. Chem. Biol. 6, 559-568. doi: 10.1016/S1074-5521(99)80088-X
56. Hashimoto-Torii, K., Torii, M., Fujimoto, M., Nakai, A., El Fatimy, R., Mezger, V., et al. (2014). Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron 82, 560-572. doi: 10.1016/j.neuron.2014.03.002
57. Hata, A. N., Yeo, A., Faber, A. C., Lifshits, E., Chen, Z., Cheng, K. A., et al. (2014). Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS mutant lung cancers. Cancer Res. 74, 3146-3156. doi: 10.1158/0008-5472.CAN-13-3728
58. Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., et al. (2010). RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431-435. doi: 10.1038/nature08833
59. Hebert, L. E., Weuve, J., Scherr, P. A., and Evans, D. A. (2013). Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 80, 1778-1783. doi: 10.1212/WNL.0b013e31828726f5
60. Heidorn, S. J., Milagre, C., Whittaker, S., Nourry, A., Niculescu-Duvas, I., Dhomen, N., et al. (2010). Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140, 209-221. doi: 10.1016/j.cell.2009.12.040
61. Hirabayashi, S., Baranski, T. J., and Cagan, R. L. (2013). Transformed Drosophila cells evade diet-mediated insulin resistance through wingless signaling. Cell 154, 664-675. doi: 10.1016/j.cell.2013.06.030
62. Hotta, A., Cheung, A. Y., Farra, N., Garcha, K., Chang, W. Y., Pasceri, P., et al. (2009). EOS lentiviral vector selection system for human induced pluripotent stem cells. Nat. Protoc. 4, 1828-1844. doi: 10.1038/nprot.2009.201
63. Huang, S., Holzel, M., Knijnenburg, T., Schlicker, A., Roepman, P., McDermott, U., et al. (2012). MED12 controls the response to multiple cancer drugs through regulation of TGF-beta receptor signaling. Cell 151, 937-950. doi: 10.1016/j.cell.2012.10.035
64. Ideker, T., Ozier, O., Schwikowski, B., and Siegel, A. F. (2002). Discovering regulatory and signalling circuits in molecular interaction networks. Bioinformatics 18(Suppl. 1), S233-S240. doi: 10.1093/bioinformatics/18.suppl_1.S233
65. Jahchan, N. S., Dudley, J. T., Mazur, P. K., Flores, N., Yang, D., Palmerton, A., et al. (2013). A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discov. 3, 1364-1377. doi: 10.1158/2159-8290.CD-13-0183
66. Jansen, R., Yu, H., Greenbaum, D., Kluger, Y., Krogan, N. J., Chung, S., et al. (2003). A Bayesian networks approach for predicting protein-protein interactions from genomic data. Science 302, 449-453. doi: 10.1126/science.1087361
67. Joseph, E. W., Pratilas, C. A., Poulikakos, P. I., Tadi, M., Wang, W., Taylor, B. S., et al. (2010). The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc. Natl. Acad. Sci. U.S.A. 107, 14903-14908. doi: 10.1073/pnas.1008990107
68. Jostins, L., Ripke, S., Weersma, R. K., Duerr, R. H., McGovern, D. P., Hui, K. Y., et al. (2012). Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124. doi: 10.1038/nature11582
69. Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., et al. (2013). Mutational landscape and significance across 12 major cancer types. Nature 502, 333-339. doi: 10.1038/nature12634
70. Kessler, R. M., Woodward, N. D., Riccardi, P., Li, R., Ansari, M. S., Anderson, S., et al. (2009). Dopamine D2 receptor levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects. Biol. Psychiatry 65, 1024-1031. doi: 10.1016/j.biopsych.2008.12.029
71. Kidd, B. A., Peters, L. A., Schadt, E. E., and Dudley, J. T. (2014). Unifying immunology with informatics and multiscale biology. Nat. Immunol. 15, 118-127. doi: 10.1038/ni.2787
72. Kola, I., and Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3, 711-715. doi: 10.1038/nrd1470
73. Konieczkowski, D. J., Johannessen, C. M., Abudayyeh, O., Kim, J. W., Cooper, Z. A., Piris, A., et al. (2014). A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov. 4, 745-748. doi: 10.1158/2159-8290.CD-13-0424
74. Kriks, S., Shim, J. W., Piao, J., Ganat, Y. M., Wakeman, D. R., Xie, Z., et al. (2011). Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480, 547-551. doi: 10.1038/nature10648
75. Kumar, M. S., Hancock, D. C., Molina-Arcas, M., Steckel, M., East, P., Diefenbacher, M., et al. (2012). The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 149, 642-655. doi: 10.1016/j.cell.2012.02.059
76. Lamba, S., Russo, M., Sun, C., Lazzari, L., Cancelliere, C., Grernrum, W., et al. (2014). RAF suppression synergizes with MEK Inhibition in KRAS Mutant Cancer Cells. Cell Rep. 8, 1475-1483. doi: 10.1016/j.celrep.2014.07.033
77. Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., et al. (2009). Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461, 402-406. doi: 10.1038/nature08320
78. Lee, I., Date, S. V., Adai, A. T., and Marcotte, E. M. (2004). A probabilistic functional network of yeast genes. Science 306, 1555-1558. doi: 10.1126/science.1099511
79. Lee, S. H., DeCandia, T. R., Ripke, S., Yang, J., Sullivan, P. F., Goddard, M. E., et al. (2012). Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat. Genet. 44, 247-250. doi: 10.1038/ng.1108
80. Lito, P., Pratilas, C. A., Joseph, E. W., Tadi, M., Halilovic, E., Zubrowski, M., et al. (2012). Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22, 668-682. doi: 10.1016/j.ccr.2012.10.009
81. Lito, P., Saborowski, A., Yue, J., Solomon, M., Joseph, E., Gadal, S., et al. (2014). Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell 25, 697-710. doi: 10.1016/j.ccr.2014.03.011
82. Lord, C. J., and Ashworth, A. (2013). Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat. Med. 19, 1381-1388. doi: 10.1038/nm.3369
83. Lum, P. Y., Chen, Y., Zhu, J., Lamb, J., Melmed, S., Wang, S., et al. (2006). Elucidating the murine brain transcriptional network in a segregating mouse population to identify core functional modules for obesity and diabetes. J. Neurochem. 97(Suppl. 1), 50-62. doi: 10.1111/j.1471-4159.2006.03661.x
84. Luo, J., Emanuele, M. J., Li, D., Creighton, C. J., Schlabach, M. R., Westbrook, T. F., et al. (2009a). A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835-848. doi: 10.1016/j.cell.2009.05.006
85. Luo, J., Solimini, N. L., and Elledge, S. J. (2009b). Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823-837. doi: 10.1016/j.cell.2009.02.024
86. Maherali, N., Sridharan, R., Xie, W., Utikal, J., Eminli, S., Arnold, K., et al. (2007). Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55-70. doi: 10.1016/j.stem.2007.05.014
87. Mair, B., Kubicek, S., and Nijman, S. M. (2014). Exploiting epigenetic vulnerabilities for cancer therapeutics. Trends Pharmacol. Sci. 35, 136-145. doi: 10.1016/j.tips.2014.01.001
88. Malhotra, D., and Sebat, J. (2012). CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148, 1223-1241. doi: 10.1016/j.cell.2012.02.039
89. Marchetto, M. C., Carromeu, C., Acab, A., Yu, D., Yeo, G. W., Mu, Y., et al. (2010). A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells. Cell 143, 527-539. doi: 10.1016/j.cell.2010.10.016
90. Mariani, J., Simonini, M. V., Palejev, D., Tomasini, L., Coppola, G., Szekely, A. M., et al. (2012). Modeling human cortical development in vitro using induced pluripotent stem cells. Proc. Natl. Acad. Sci. U.S.A. 109, 12770-12775. doi: 10.1073/pnas.1202944109
91. Maroof, A. M., Keros, S., Tyson, J. A., Ying, S. W., Ganat, Y. M., Merkle, F. T., et al. (2013). Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12, 559-572. doi: 10.1016/j.stem.2013.04.008
92. McCabe, N., Lord, C. J., Tutt, A. N., Martin, N. M., Smith, G. C., and Ashworth, A. (2005). BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of Poly (ADP-Ribose) polymerase: an issue of potency. Cancer Biol. Ther. 4, 934-936. doi: 10.4161/cbt.4.9.2141
93. McCarroll, S. A., Kuruvilla, F. G., Korn, J. M., Cawley, S., Nemesh, J., Wysoker, A., et al. (2008). Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166-1174. doi: 10.1038/ng.238
94. McDermott, U., Iafrate, A. J., Gray, N. S., Shioda, T., Classon, M., Maheswaran, S., et al. (2008). Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res. 68, 3389-3395. doi: 10.1158/0008-5472.CAN-07-6186
95. Mehrabian, M., Allayee, H., Stockton, J., Lum, P. Y., Drake, T. A., Castellani, L. W., et al. (2005). Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits. Nat. Genet. 37, 1224-1233. doi: 10.1038/ng1619
96. Meissner, A., Wernig, M., and Jaenisch, R. (2007). Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat. Biotechnol. 25, 1177-1181. doi: 10.1038/nbt1335
97. Millstein, J., Zhang, B., Zhu, J., and Schadt, E. E. (2009). Disentangling molecular relationships with a causal inference test. BMC Genet. 10:23. doi: 10.1186/1471-2156-10-23
98. Muellner, M. K., Uras, I. Z., Gapp, B. V., Kerzendorfer, C., Smida, M., Lechtermann, H., et al. (2011). A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer. Nat. Chem. Biol. 7, 787-793. doi: 10.1038/nchembio.695
99. Muller, F. L., Colla, S., Aquilanti, E., Manzo, V. E., Genovese, G., Lee, J., et al. (2012). Passenger deletions generate therapeutic vulnerabilities in cancer. Nature 488, 337-342. doi: 10.1038/nature11331
100. National Research Council (US) Committee on A Framework for Developing a New Taxonomy of Disease. (2011). Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. Washington, DC, National Academies Press.
101. Ng, M. Y., Levinson, D. F., Faraone, S. V., Suarez, B. K., DeLisi, L. E., Arinami, T., et al. (2009). Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Mol. Psychiatry 14, 774-785. doi: 10.1038/mp.2008.135
102. Nguyen, H. N., Byers, B., Cord, B., Shcheglovitov, A., Byrne, J., Gujar, P., et al. (2011). LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267-280. doi: 10.1016/j.stem.2011.01.013
103. Nicholas, C. R., Chen, J., Tang, Y., Southwell, D. G., Chalmers, N., Vogt, D., et al. (2013). Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12, 573-586. doi: 10.1016/j.stem.2013.04.005
104. Niederst, M. J., and Engelman, J. A. (2013). Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci. Signal. 6:re6. doi: 10.1126/scisignal.2004652
105. O'Hare, T., Deininger, M. W., Eide, C. A., Clackson, T., and Druker, B. J. (2011). Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin. Cancer Res. 17, 212-221. doi: 10.1158/1078-0432.CCR-09-3314
106. Paez, J. G., Janne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497-1500. doi: 10.1126/science.1099314
107. Pang, Z. P., Yang, N., Vierbuchen, T., Ostermeier, A., Fuentes, D. R., Yang, T. Q., et al. (2011). Induction of human neuronal cells by defined transcription factors. Nature 476, 220-223. doi: 10.1038/nature10202
108. Park, I. H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., et al. (2008). Disease-specific induced pluripotent stem cells. Cell 134, 877-886. doi: 10.1016/j.cell.2008.07.041
109. Pasca, S. P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Pasca, A. M., et al. (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med. 17, 1657-1662. doi: 10.1038/nm.2576
110. Patil, S. T., Zhang, L., Martenyi, F., Lowe, S. L., Jackson, K. A., Andreev, B. V., et al. (2007). Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med. 13, 1102-1107. doi: 10.1038/nm1632
111. Paulsen, B. D., Maciel, R. D., Galina, A., da Silveira, M. S., Souza, C. D., Drummond, H., et al. (2011). Altered oxygen metabolism associated to neurogenesis of induced pluripotent stem cells derived from a schizophrenic patient. Cell Transplant. 21, 1547-1559. doi: 10.3727/096368911X600957
112. Poels, E. M., Kegeles, L. S., Kantrowitz, J. T., Slifstein, M., Javitt, D. C., Lieberman, J. A., et al. (2014). Imaging glutamate in schizophrenia: review of findings and implications for drug discovery. Mol. Psychiatry 19, 20-29. doi: 10.1038/mp.2013.136
113. Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., and Rosen, N. (2010). RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464, 427-430. doi: 10.1038/nature08902
114. Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., et al. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100-103. doi: 10.1038/nature10868
115. Purcell, S., Moran, J., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., et al. (2014). A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185-190. doi: 10.1038/nature12975
116. Purcell, S. M., Wray, N. R., Stone, J. L., Visscher, P. M., O'Donovan, M. C., Sullivan, P. F., et al. (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748-752. doi: 10.1038/nature08185
117. Rehman, F. L., Lord, C. J., and Ashworth, A. (2010). Synthetic lethal approaches to breast cancer therapy. Nat. Rev. Clin. Oncol. 7, 718-724. doi: 10.1038/nrclinonc.2010.172
118. Riabinska, A., Daheim, M., Herter-Sprie, G. S., Winkler, J., Fritz, C., Hallek, M., et al. (2013). Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors. Sci. Transl. Med. 5:189ra178. doi: 10.1126/scitranslmed.3005814
119. Rikova, K., Guo, A., Zeng, Q., Possemato, A., Yu, J., Haack, H., et al. (2007). Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131, 1190-1203. doi: 10.1016/j.cell.2007.11.025
120. Ripke, S., O'Dushlaine, C., Chambert, K., Moran, J. L., Kahler, A. K., Akterin, S., et al. (2013). Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45, 1150-1159. doi: 10.1038/ng.2742
121. Ripke, S., Sanders, A. R., Kendler, K. S., Levinson, D. F., Sklar, P., Holmans, P. A., et al. (2011). Genome-wide association study identifies five new schizophrenia loci. Nat. Genet. 43, 969-976. doi: 10.1038/ng.940
122. Robert, C., Thomas, L., Bondarenko, I., O'Day, S., Jeffrey Weber, M. D., Garbe, C., et al. (2011). Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517-2526. doi: 10.1056/NEJMoa1104621
123. Robicsek, O., Karry, R., Petit, I., Salman-Kesner, N., Muller, F. J., Klein, E., et al. (2013). Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol. Psychiatry 18, 1067-1076. doi: 10.1038/mp.2013.67
124. Roller, D. G., Axelrod, M., Capaldo, B. J., Jensen, K., Mackey, A., Weber, M. J., et al. (2012). Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma. Mol. Cancer Ther. 11, 2505-2515. doi: 10.1158/1535-7163.MCT-12-0461
125. Rudin, C. M., Hann, C. L., Laterra, J., Yauch, R. L., Callahan, C. A., Fu, L., et al. (2009). Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N. Engl. J. Med. 361, 1173-1178. doi: 10.1056/NEJMoa0902903
126. Schadt, E. E. (2005). Exploiting naturally occurring DNA variation and molecular profiling data to dissect disease and drug response traits. Curr. Opin. Biotechnol. 16, 647-654. doi: 10.1016/j.copbio.2005.10.005
127. Schadt, E. E. (2009). Molecular networks as sensors and drivers of common human diseases. Nature 461, 218-223. doi: 10.1038/nature08454
128. Schadt, E. E., Friend, S. H., and Shaywitz, D. A. (2009). A network view of disease and compound screening. Nat. Rev. Drug Discov. 8, 286-295. doi: 10.1038/nrd2826
129. Schadt, E. E., Lamb, J., Yang, X., Zhu, J., Edwards, S., Guhathakurta, D., et al. (2005). An integrative genomics approach to infer causal associations between gene expression and disease. Nat. Genet. 37, 710-717. doi: 10.1038/ng1589
130. Schadt, E. E., Molony, C., Chudin, E., Hao, K., Yang, X., Lum, P. Y., et al. (2008). Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6:e107. doi: 10.1371/journal.pbio.0060107
131. Schadt, E. E., Monks, S. A., Drake, T. A., Lusis, A. J., Che, N., Colinayo, V., et al. (2003). Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297-302. doi: 10.1038/nature01434
132. Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421-427. doi: 10.1038/nature13595
133. Schmit, F., Utermark, T., Zhang, S., Wang, Q., Von, T., Roberts, T. M., et al. (2014). PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc. Natl. Acad. Sci. U.S.A. 111, 6395-6400. doi: 10.1073/pnas.1323004111
134. Shi, J., Levinson, D. F., Duan, J., Sanders, A. R., Zheng, Y., Pe'er, I., et al. (2009). Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753-757. doi: 10.1038/nature08192
135. Shi, Y., Kirwan, P., Smith, J., Robinson, H. P., and Livesey, F. J. (2012). Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat. Neurosci. 15, 477-486. doi: 10.1038/nn.3041
136. Sirota, M., Dudley, J. T., Kim, J., Chiang, A. P., Morgan, A. A., Sweet-Cordero, A., et al. (2011). Discovery and preclinical validation of drug indications using compendia of public gene expression data. Sci. Transl. Med. 3:96ra77. doi: 10.1126/scitranslmed.3001318
137. Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., et al. (2007). Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561-566. doi: 10.1038/nature05945
138. Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G. W., Cook, E. G., et al. (2009). Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964-977. doi: 10.1016/j.cell.2009.02.013
139. Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G., Basso, A., et al. (2006). BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358-362. doi: 10.1038/nature04304
140. Stefansson, H., Ophoff, R. A., Steinberg, S., Andreassen, O. A., Cichon, S., Rujescu, D., et al. (2009). Common variants conferring risk of schizophrenia. Nature 460, 744-747. doi: 10.1038/nature08186
141. Steinberg, S., de Jong, S., Mattheisen, M., Costas, J., Demontis, D., Jamain, S., et al. (2014). Common variant at 16p11.2 conferring risk of psychosis. Mol. Psychiatry 19, 108-114. doi: 10.1038/mp.2012.157
142. Stratton, M. R. (2011). Exploring the genomes of cancer cells: progress and promise. Science 331, 1553-1558. doi: 10.1126/science.1204040
143. Sullivan, P. F., Kendler, K. S., and Neale, M. C. (2003). Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187-1192. doi: 10.1001/archpsyc.60.12.1187
144. Sun, C., Hobor, S., Bertotti, A., Zecchin, D., Huang, S., Galimi, F., et al. (2014). Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep. 7, 86-93. doi: 10.1016/j.celrep.2014.02.045
145. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872. doi: 10.1016/j.cell.2007.11.019
146. Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676. doi: 10.1016/j.cell.2006.07.024
147. Topalian, S. L., Sznol, M., McDermott, D. F., Kluger, H. M., Carvajal, R. D., Sharfman, W. H., et al. (2014). Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020-1030. doi: 10.1200/JCO.2013.53.0105
148. Toyoshima, M., Howie, H. L., Imakura, M., Walsh, R. M., Annis, J. E., Chang, A. N., et al. (2012). Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc. Natl. Acad. Sci. U.S.A. 109, 9545-9550. doi: 10.1073/pnas.1121119109
149. Traer, E., Javidi-Sharifi, N., Agarwal, A., Dunlap, J., English, I., Martinez, J., et al. (2014). Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations. Blood 123, 1516-1524. doi: 10.1182/blood-2013-07-518381
150. Tran, L. M., Zhang, B., Zhang, Z., Zhang, C., Xie, T., Lamb, J. R., et al. (2011). Inferring causal genomic alterations in breast cancer using gene expression data. BMC Syst. Biol. 5:121. doi: 10.1186/1752-0509-5-121
151. Turner, N. C., Lord, C. J., Iorns, E., Brough, R., Swift, S., Elliott, R., et al. (2008). A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. EMBO J. 27, 1368-1377. doi: 10.1038/emboj.2008.61
152. van't Veer, L. J., Dai, H., van de Vijver, M. J., He, Y. D., Hart, A. A., Mao, M., et al. (2002). Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530-536. doi: 10.1038/415530a
153. Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Sudhof, T. C., and Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035-1041. doi: 10.1038/nature08797
154. Von Hoff, D. D., LoRusso, P. M., Rudin, C. M., Reddy, J. C., Yauch, R. L., Tibes, R., et al. (2009). Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 361, 1164-1172. doi: 10.1056/NEJMoa0905360
155. Wang, I. M., Zhang, B., Yang, X., Zhu, J., Stepaniants, S., Zhang, C., et al. (2012). Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers. Mol. Syst. Biol. 8, 594. doi: 10.1038/msb.2012.24
156. Wang, S., Yehya, N., Schadt, E. E., Wang, H., Drake, T. A., and Lusis, A. J. (2006). Genetic and genomic analysis of a fat mass trait with complex inheritance reveals marked sex specificity. PLoS Genet. 2:e15. doi: 10.1371/journal.pgen.0020015
157. Weinberger, D. R. (1987). Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44, 660-669. doi: 10.1001/archpsyc.1987.01800190080012
158. Wells, S. A. Jr., Gosnell, J. E., Gagel, R. F., Moley, J., Pfister, D., Sosa, J. A., et al. (2010). Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J. Clin. Oncol. 28, 767-772. doi: 10.1200/JCO.2009.23.6604
159. Wen, L., Lu, Y. S., Zhu, X. H., Li, X. M., Woo, R. S., Chen, Y. J., et al. (2010). Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc. Natl. Acad. Sci. U.S.A. 107, 1211-1216. doi: 10.1073/pnas.0910302107
160. Wen, Z., Nguyen, H. N., Guo, Z., Lalli, M. A., Wang, X., Su, Y., et al. (2014). Synaptic dysregulation in a human iPS cell model of mental disorders. Nature doi: 10.1038/nature13716 [Epub ahead of print].
161. Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., et al. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318-324. doi: 10.1038/nature05944
162. Whitehurst, A. W., Bodemann, B. O., Cardenas, J., Ferguson, D., Girard, L., Peyton, M., et al. (2007). Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 446, 815-819. doi: 10.1038/nature05697
163. Yadav, V., Zhang, X., Liu, J., Estrem, S., Li, S., Gong, X. Q., et al. (2012). Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J. Biol. Chem. 287, 28087-28098. doi: 10.1074/jbc. M112.377218
164. Yang, X., Deignan, J. L., Qi, H., Zhu, J., Qian, S., Zhong, J., et al. (2009). Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Nat. Genet. 41, 415-423. doi: 10.1038/ng.325
165. Yang, X., Peterson, L., Thieringer, R., Deignan, J. L., Wang, X., Zhu, J., et al. (2010). Identification and validation of genes affecting aortic lesions in mice. J. Clin. Invest. 120, 2414-2422. doi: 10.1172/JCI42742
166. Yauch, R. L., Dijkgraaf, G. J., Alicke, B., Januario, T., Ahn, C. P., Holcomb, T., et al. (2009). Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326, 572-574. doi: 10.1126/science.1179386
167. Yoo, A. S., Sun, A. X., Li, L., Shcheglovitov, A., Portmann, T., Li, Y., et al. (2011). MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476, 228-231. doi: 10.1038/nature10323
168. Yu, D. X., Di Giorgio, F. P., Yao, J., Marchetto, M. C., Brennand, K., Wright, R., et al. (2014). Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Reports 2, 295-310. doi: 10.1016/j.stemcr.2014.01.009
169. Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920. doi: 10.1126/science.1151526
170. Zhang, B., Gaiteri, C., Bodea, L. G., Wang, Z., McElwee, J., Podtelezhnikov, A. A., et al. (2013a). Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707-720. doi: 10.1016/j.cell.2013.03.030
171. Zhang, Y., Pak, C., Han, Y., Ahlenius, H., Zhang, Z., Chanda, S., et al. (2013b). Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78, 785-798. doi: 10.1016/j.neuron.2013.05.029
172. Zhang, J., Fujimoto, J., Zhang, J., Wedge, D. C., Song, X., Zhang, J., et al. (2014a). Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346, 256-259. doi: 10.1126/science.1256930
173. Zhang, L., Song, X., Mohri, Y., and Qiao, L. (2014b). Role pf inflammation and tumor microenvironment in the development of gastrointestinal cancers: what induced pluripotent stem cells can do? Curr. Stem Cell Res. Ther. doi: 10.2174/1574888X09666140812112305 [Epub ahead of print].
174. Zhong, H., Beaulaurier, J., Lum, P. Y., Molony, C., Yang, X., Macneil, D. J., et al. (2010a). Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes. PLoS Genet. 6:e1000932. doi: 10.1371/journal.pgen.1000932
175. Zhong, H., Yang, X., Kaplan, L. M., Molony, C., and Schadt, E. E. (2010b). Integrating pathway analysis and genetics of gene expression for genome-wide association studies. Am. J. Hum. Genet. 86, 581-591. doi: 10.1016/j.ajhg.2010.02.020
176. Zhou, P., Shaffer, D. R., Alvarez Arias, D. A., Nakazaki, Y., Pos, W., Torres, A. J., et al. (2014). In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature 506, 52-57. doi: 10.1038/nature12988
177. Zhu, J., Chen, Y., Leonardson, A. S., Wang, K., Lamb, J. R., Emilsson, V., et al. (2010). Characterizing dynamic changes in the human blood transcriptional network. PLoS Comput. Biol. 6:e1000671. doi: 10.1371/journal.pcbi.1000671
178. Zhu, J., Lum, P. Y., Lamb, J., GuhaThakurta, D., Edwards, S. W., Thieringer, R., et al. (2004). An integrative genomics approach to the reconstruction of gene networks in segregating populations. Cytogenet. Genome Res. 105, 363-374. doi: 10.1159/000078209
179. Zhu, J., Sova, P., Xu, Q., Dombek, K. M., Xu, E. Y., Vu, H., et al. (2012). Stitching together multiple data dimensions reveals interacting metabolomic and transcriptomic networks that modulate cell regulation. PLoS Biol. 10:e1001301. doi: 10.1371/journal.pbio.1001301
180. Zhu, J., Wiener, M. C., Zhang, C., Fridman, A., Minch, E., Lum, P. Y., et al. (2007). Increasing the power to detect causal associations by combining genotypic and expression data in segregating populations. PLoS Comput. Biol. 3:e69. doi: 10.1371/journal.pcbi.0030069
181. Zhu, J., Zhang, B., Smith, E. N., Drees, B., Brem, R. B., Kruglyak, L., et al. (2008). Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks. Nat. Genet. 40, 854-861. doi: 10.1038/ng.167