Reverse engineering gene networks to identify key drivers of complex disease phenotypes

Journal of Lipid Research

Volumn 47, Issue 12, 2006, Pages 2601-2613

  Schadt, Eric E ^a   Lum, Pek Y ^a  

^a ROSETTA INPHARMATICS   (United States)

Author keywords

Genetical genomics; Networks; Systems biology

Indexed keywords

MESSENGER RNA;

ATHEROSCLEROSIS; ENVIRONMENTAL FACTOR; GENE DELETION; GENE EXPRESSION; GENE IDENTIFICATION; GENE INTERACTION; GENE TARGETING; GENETIC ENGINEERING; GENETIC SUSCEPTIBILITY; HEART INFARCTION; HUMAN; HYPERTENSION; MOLECULAR INTERACTION; NONHUMAN; OBESITY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN INTERACTION; QUANTITATIVE TRAIT LOCUS; REVIEW; ANIMAL; BIOLOGICAL MODEL; CARDIOVASCULAR DISEASE; GENETICS; GENOMICS; METABOLIC DISORDER; METABOLISM; SYSTEMS BIOLOGY;

ANIMALS; CARDIOVASCULAR DISEASES; GENETIC ENGINEERING; GENOMICS; HUMANS; METABOLIC DISEASES; MODELS, BIOLOGICAL; PHENOTYPE; SYSTEMS BIOLOGY;

EID: 33845569346     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.R600026-JLR200     Document Type: Review

References (72)

1. Florez, J. C., K. A. Jablonski, N. Bayley, T. I. Pollin, P. I. de Bakker, A. R. Shuldiner, W. C. Knowler, D. M. Nathan, and D. Altshuler. 2006. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N. Engl. J. Med. 355: 241-250.
2. Grant, S. F., G. Thorleifsson, I. Reynisdottir, R. Benediktsson, A. Manolescu, J. Sainz, A. Helgason, H. Stefansson, V. Emilsson, A. Helgadottir, et al. 2006. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat. Genet. 38: 320-323.
3. Herbert, A., N. P. Gerry, M. B. McQueen, I. M. Heid, A. Pfeufer, T. Illig, H. E. Wichmann, T. Meitinger, D. Hunter, F. B. Hu, et al. 2006. A common genetic variant is associated with adult and childhood obesity. Science. 312: 279-283.
4. Edwards, A. O., R. Ritter 3rd, K. J. Abel, A. Manning, C. Panhuysen, and L. A. Farrer. 2005. Complement factor H polymorphism and age-related macular degeneration. Science. 308: 421-424.
5. Haines, J. L., M. A. Hauser, S. Schmidt, W. K. Scott, L. M. Olson, P. Gallins, K. L. Spencer, S. Y. Kwan, M. Noureddine, J. R. Gilbert, et al. 2005. Complement factor H variant increases the risk of age-related macular degeneration. Science. 308: 419-421.
6. Klein, R. J., C. Zeiss, E. Y. Chew, J. Y. Tsai, R. S. Sackler, C. Haynes, A. K. Henning, J. P. SanGiovanni, S. M. Mane, S. T. Mayne, et al. 2005. Complement factor H polymorphism in age-related macular degeneration. Science. 308: 385-389.
7. Li, M., P. Atmaca-Sonmez, M. Othman, K. E. Branham, R. Khanna, M. S. Wade, Y. Li, L. Liang, S. Zareparsi, A. Swaroop, et al. 2006. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat. Genet. 38: 1049-1054.
8. Maller, J., S. George, S. Purcell, J. Fagerness, D. Altshuler, M. J. Daly, and J. M. Seddon. 2006. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat. Genet. 38: 1055-1059.
9. Dwyer, J. H., H. Allayee, K. M. Dwyer, J. Fan, H. Wu, R. Mar, A. J. Lusis, and M. Mehrabian. 2004. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N. Engl. J. Med. 350: 29-37.
10. Mehrabian, M., H. Allayee, J. Wong, W. Shi, X. P. Wang, Z. Shaposhnik, C. D. Funk, and A. J. Lusis. 2002. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ. Res. 91: 120-126.
11. Zhao, L., M. P. Moos, R. Grabner, F. Pedrono, J. Fan, B. Kaiser, N. John, S. Schmidt, R. Spanbroek, K. Lotzer, et al. 2004. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat. Med. 10: 966-973.
12. Mehrabian, M., H. Allayee, J. Stockton, P. Y. Lum, T. A. Drake, L. W. Castellani, M. Suh, C. Armour, S. Edwards, J. Lamb, 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.
13. Schadt, E. E., J. Lamb, X. Yang, J. Zhu, S. Edwards, D. Guhathakurta, S. K. Sieberts, S. Monks, M. Reitman, C. Zhang, et al. 2005. An integrative genomics approach to infer causal associations between gene expression and disease. Nat. Genet. 37: 710-717.
14. Schadt, E. E., A. Sachs, and S. Friend. 2005. Embracing complexity, inching closer to reality. Sci. STKE. 295: pe40.
15. Hartwell, L. H., J. J. Hopfield, S. Leibler, and A. W. Murray. 1999. From molecular to modular cell biology. Nature. 402: C47-C52.
16. Barabasi, A. L., and Z. N. Oltvai. 2004. Network biology: understanding the cell's functional organization. Nat. Rev. Genet. 5: 101-113.
17. Zerhouni, E. 2003. Medicine. The NIH roadmap. Science. 302: 63-72.
18. Han, J. D., N. Bertin, T. Hao, D. S. Goldberg, G. F. Berriz, L. V. Zhang, D. Dupuy, A. J. Walhout, M. E. Cusick, F. P. Roth, et al. 2004. Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature. 430: 88-93.
19. Luscombe, N. M., M. M. Babu, H. Yu, M. Snyder, S. A. Teichmann, and M. Gerstein. 2004. Genomic analysis of regulatory network dynamics reveals large topological changes. Nature. 431: 308-312.
20. Pinto, S., A. G. Roseberry, H. Liu, S. Diano, M. Shanabrough, X. Cai, J. M. Friedman, and T. L. Horvath. 2004. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science. 304: 110-115.
21. Zhu, J., P. Y. Lum, J. Lamb, D. GuhaThakurta, S. W. Edwards, R. Thieringer, J. P. Berger, M. S. Wu, J. Thompson, A. B. Sachs, et al. (2004). An integrative genomics approach to the reconstruction of gene networks in segregating populations. Cytogenet. Genome Res. 105: 363-374.
22. Rual, J. F., K. Venkatesan, T. Hao, T. Hirozane-Kishikawa, A. Dricot, N. Li, G. F. Berriz, F. D. Gibbons, M. Dreze, N. Ayivi-Guedehoussou, et al. 2005. Towards a proteome-scale map of the human protein-protein interaction network. Nature. 437: 1173-1178.
23. Gargalovic, P. S., M. Imura, B. Zhang, N. M. Gharavi, M. J. Clark, J. Pagnon, W. P. Yang, A. He, A. Truong, S. Patel, et al. 2006. Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids. Proc. Natl. Acad. Sci. USA. 103: 12741-12746.
24. Ghazalpour, A., S. Doss, B. Zhang, S. Wang, C. Plaisier, R. Castellanos, A. Brozell, E. E. Schadt, T. A. Drake, A. J. Lusis, et al. Integrating genetic and network analysis to characterize genes related to mouse weight. PLoS Genet. Epub ahead of print. August 18, 2006; doi:10.1371/journal.pgen.0020130.
25. Barabasi, A. L., and R. Albert. 1999. Emergence of scaling in random networks. Science. 286: 509-512.
26. Gunsalus, K. C., H. Ge, A. J. Schetter, D. S. Goldberg, J. D. Han, T. Hao, G. F. Berriz, N. Bertin, J. Huang, L. S. Chuang, et al. 2005. Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis. Nature. 436: 861-865.
27. Ravasz, E., A. L. Somera, D. A. Mongru, Z. N. Oltvai, and A. L. Barabasi. 2002. Hierarchical organization of modularity in metabolic networks. Science. 297: 1551-1555.
28. Carlson, M. R., B. Zhang, Z. Fang, P. S. Mischel, S. Horvath, and S. F. Nelson. 2006. Gene connectivity, function, and sequence conservation: predictions from modular yeast co-expression networks. BMC Genomics. 7: 40.
29. Li, H., H. Chen, L. Bao, K. F. Manly, E. J. Chesler, L. Lu, J. Wang, M. Zhou, R. W. Williams, and Y. Cui. 2006. Integrative genetic analysis of transcription modules: towards filling the gap between genetic loci and inherited traits. Hum. Mol. Genet. 15: 481-492.
30. Zhang, B., and S. Horvath. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. Vol. 4: No. 1, Article 17 Accessed October 20, 2006, at http://www.bepress.com/sagmb/vol4/iss1/ art17.
31. Wang, S., N. Yehya, E. E. Schadt, H. Wang, T. A. Drake, and A. J. Lusis. 2006. Genetic and genomic analysis of a fat mass trait with complex inheritance reveals marked sex specificity. PLoS Genet. 2: e15.
32. Yang, X., E. E. Schadt, S. Wang, H. Wang, A. P. Arnold, L. Ingram-Drake, T. A. Drake, and A. J. Lusis. 2006. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 16: 995-1004.
33. Cervino, A. C., G. Li, S. Edwards, J. Zhu, C. Laurie, G. Tokiwa, P. Y. Lum, S. Wang, L. W. Castellini, A. J. Lusis, et al. 2005. Integrating QTL and high-density SNP analyses in mice to identify Insig2 as a susceptibility gene for plasma cholesterol levels. Genomics. 86: 505-517.
34. Hughes, T. R., M. J. Marton, A. R. Jones, C. J. Roberts, R. Stoughton, C. D. Armour, H. A. Bennett, E. Coffey, H. Dai, Y. D. He, et al. 2000. Functional discovery via a compendium of expression profiles. Cell. 102: 109-126.
35. Legato, M. J., A. Gelzer, R. Goland, S. A. Ebner, S. Rajan, V. Villagra, and M. Kosowski. 2006. Gender-specific care of the patient with diabetes: review and recommendations. Gend. Med. 3: 131-158.
36. Nathan, L., and G. Chaudhuri. 1997. Estrogens and atherosclerosis. Annu. Rev. Pharmacol. Toxicol. 37: 477-515.
37. Regitz-Zagrosek, V. 2006. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat. Rev. Drug Discov. 5: 425-438.
38. Di Marco, F., M. Verga, M. Reggente, F. Maria Casanova, P. Santus, F. Blasi, L. Allegra, and S. Centanni. 2006. Anxiety and depression in COPD patients: the roles of gender and disease severity. Respir. Med. 100: 1767-1774.
39. Goldberg, A. C. 2004. A meta-analysis of randomized controlled studies on the effects of extended-release niacin in women. Am. J. Cardiol. 94: 121-124.
40. Smesny, S., T. Rosburg, S. Klemm, S. Riemann, K. Baur, N. Rudolph, S. Grunwald, and H. Sauer. 2004. The influence of age and gender on niacin skin test results - implications for the use as a biochemical marker in schizophrenia. J. Psychiatr. Res. 38: 537-543.
41. Kendziorski, C. M., M. Chen, M. Yuan, H. Lan, and A. D. Attie. 2006. Statistical methods for expression quantitative trait loci (eQTL) mapping. Biometrics. 62: 19-27.
42. Storey, J. D., J. Y. Dai, and J. T. Leek. The optimal discovery procedure for large-scale significance testing, with applications to comparative microarray experiments. Biostatistics. Epub ahead of print. August 23, 2006; doi: 10.1093/biostatistics/kxl019.
43. Storey, J. D., W. Xiao, J. T. Leek, R. G. Tompkins, and R. W. Davis. 2005. Significance analysis of time course microarray experiments. Proc. Natl. Acad. Sci. USA. 102: 12837-12842.
44. Brem, R. B., G. Yvert, R. Clinton, and L. Kruglyak. 2002. Genetic dissection of transcriptional regulation in budding yeast. Science. 296: 752-755.
45. DeCook, R., S. Lall, D. Nettleton, and S. H. Howell. 2006. Genetic regulation of gene expression during shoot development in Arabidopsis. Genetics. 172: 1155-1164.
46. Hubner, N., C. A. Wallace, H. Zimdahl, E. Petretto, H. Schulz, F. Maciver, M. Mueller, O. Hummel, J. Monti, V. Zidek, et al. 2005. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat. Genet. 37: 243-253.
47. Jin, W., R. M. Riley, R. D. Wolfinger, K. P. White, G. Passador-Gurgel, and G. Gibson. 2001. The contributions of sex, genotype and age to transcriptional variance in Drosophila melanogaster. Nat. Genet. 29: 389-395.
48. Klose, J., C. Nock, M. Herrmann, K. Stuhler, K. Marcus, M. Bluggel, E. Krause, L. C. Schalkwyk, S. Rastan, S. D. Brown, et al. 2002. Genetic analysis of the mouse brain proteome. Nat. Genet. 30: 385-393.
49. Monks, S. A., A. Leonardson, H. Zhu, P. Cundiff, P. Pietrusiak, S. Edwards, J. W. Phillips, A. Sachs, and E. E. Schadt. 2004. Genetic inheritance of gene expression in human cell lines. Am. J. Hum. Genet. 75: 1094-1105.
50. Morley, M., C. M. Molony, T. M. Weber, J. L. Devlin, K. G. Ewens, R. S. Spielman, and V. G. Cheung. 2004. Genetic analysis of genome-wide variation in human gene expression. Nature. 430: 743-747.
51. Oleksiak, M. F., G. A. Churchill, and D. L. Crawford. 2002. Variation in gene expression within and among natural populations. Nat. Genet. 32: 261-266.
52. Schadt, E. E., S. A. Monks, T. A. Drake, A. J. Lusis, N. Che, V. Colinayo, T. G. Ruff, S. B. Milligan, J. R. Lamb, G. Cavet, et al. 2003. Genetics of gene expression surveyed in maize, mouse and man. Nature. 422: 297-302.
53. Stranger, B. E., M. S. Forrest, A. G. Clark, M. J. Minichiello, S. Deutsch, R. Lyle, S. Hunt, B. Kahl, S. E. Antonarakis, S. Tavare, et al. 2005. Genome-wide associations of gene expression variation in humans. PLoS Genet. 1: e78.
54. Yvert, G., R. B. Brem, J. Whittle, J. M. Akey, E. Foss, E. N. Smith, R. Mackelprang, and L. Kruglyak. 2003. Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nat. Genet. 35: 57-64.
55. Kulp, D. C., and M. Jagalur. 2006. Causal inference of regulator-target pairs by gene mapping of expression phenotypes. BMC Genomics. 7: 125.
56. Lum, P. Y., Y. Chen, J. Zhu, J. Lamb, S. Melmed, S. Wang, T. A. Drake, A. J. Lusis, and E. E. Schadt. 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.): 50-62.
57. Pearl, J. 1988. Probabilistic Reasoning in Intelligent Systems: Networks of Plausible Inference. Morgan Kaufmann Publishers, San Mateo, CA.
58. Pearl, J. 2000. Causality. Cambridge University Press, New York, NY.
59. Chesler, E. J., L. Lu, S. Shou, Y. Qu, J. Gu, J. Wang, H. C. Hsu, J. D. Mountz, N. E. Baldwin, M. A. Langston, et al. 2005. Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat. Genet. 37: 233-242.
60. Cheung, V. G., R. S. Spielman, K. G. Ewens, T. M. Weber, M. Morley, and J. T. Burdick. 2005. Mapping determinants of human gene expression by regional and genome-wide association. Nature. 437: 1365-1369.
61. 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.
62. Schadt, E. E. 2006. Novel integrative genomics strategies to identify genes for complex traits. Anim. Genet. 37(Suppl.): 18-23.
63. Lee, S., D. Pe'er, A. M. Dudley, G. M. Church, and D. Koller. 2006. Identifying regulatory mechanisms using individual variation reveals key role for chromatin modification. Proc. Natl. Acad. Sci. USA. 103: 14062-14067.
64. Stylianou, I. M., R. Korstanje, R. Li, S. Sheehan, B. Paigen, and G. A. Churchill. 2006. Quantitative trait locus analysis for obesity reveals multiple networks of interacting loci. Mamm. Genome. 17: 22-36.
65. Bystrykh, L., E. Weersing, B. Dontje, S. Sutton, M. T. Pletcher, T. Wiltshire, A. I. Su, E. Vellenga, J. Wang, K. F. Manly, et al. 2005. Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'. Nat. Genet. 37: 225-232.
66. Ghazalpour, A., S. Doss, S. S. Sheth, L. A. Ingram-Drake, E. E. Schadt, A. J. Lusis, and T. A. Drake. 2005. Genomic analysis of metabolic pathway gene expression in mice. Genome Biol. 6: R59.
67. van't Veer, L. J., H. Dai, M. J. van de Vijver, Y. D. He, A. A. Hart, M. Mao, H. L. Peterse, K. van der Kooy, M. J. Marton, A. T. Witteveen, et al. 2002. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 415: 530-536.
68. Ballantyne, C. M., N. Abate, Z. Yuan, T. R. King, and J. Palmisano. 2005. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. Am. Heart J. 149: 464-473.
69. Yeh, P., A. I. Tschumi, and R. Kishony. 2006. Functional classification of drugs by properties of their pairwise interactions. Nat. Genet. 38: 489-494.
70. Li, C. X., A. Parker, E. Menocal, S. Xiang, L. Borodyansky, and J. H. Fruehauf. 2006. Delivery of RNA interference. Cell Cycle. 5: 2103-2109.
71. Anway, M. D., A. S. Cupp, M. Uzumcu, and M. K. Skinner. 2005. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 308: 1466-1469.
72. Doss, S., E. E. Schadt, T. A. Drake, and A. J. Lusis. 2005. Cis-acting expression quantitative trait loci in mice. Genome Res. 15: 681-691.