A model-driven methodology for exploring complex disease comorbidities applied to autism spectrum disorder and inflammatory bowel disease

Journal of Biomedical Informatics

Volumn 63, Issue , 2016, Pages 366-378

  Somekh, Judith ^a,b   Peleg, Mor ^b   Eran, Alal ^a,g,h   Koren, Itay ^a,c,d   Feiglin, Ariel ^a   Demishtein, Alik ^e   Shiloh, Ruth ^e   Heiner, Monika ^f   Kong, Sek Won ^g   Elazar, Zvulun ^e   Kohane, Isaac ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF HAIFA   (Israel)

^c BRIGHAM AND WOMEN S HOSPITAL   (United States)

^d HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^e WEIZMANN INSTITUTE OF SCIENCE   (Israel)

^f BRANDENBURG UNIVERSITY OF TECHNOLOGY   (Germany)

^g BOSTON CHILDREN S HOSPITAL   (United States)

^h BEN GURION UNIVERSITY OF THE NEGEV   (Israel)

Author keywords

ASD; Autism; Autophagy; IBD; Modeling; Petri nets

Indexed keywords

COMPLEX NETWORKS; MODELS; PETRI NETS; STOCHASTIC SYSTEMS;

AUTISM; AUTISM SPECTRUM DISORDERS; AUTOPHAGY; CO-MORBID CONDITIONS; INFLAMMATORY BOWEL DISEASE; MODEL-DRIVEN METHODOLOGY; MOLECULAR PATHWAYS; STOCHASTIC PETRI NETS;

DISEASES;

ARTICLE; ATG16L1 GENE; ATG2A GENE; ATG7 GENE; AUTISM; AUTOPHAGY; CELL SURVIVAL; COMORBIDITY; COMPARATIVE COMORBIDITIES SIMULATION; COMPUTER MODEL; CONVERGENT EVOLUTION; DISEASE ASSOCIATION; ENDOPLASMIC RETICULUM STRESS; GABARAPL1 GENE; GENE; GENE ONTOLOGY; GENETIC ASSOCIATION; GENETIC RISK; GENOTYPE PHENOTYPE CORRELATION; HUMAN; INFLAMMATORY BOWEL DISEASE; IRGM GENE; LOSS OF FUNCTION MUTATION; METHODOLOGY; MODEL DRIVEN METHODOLOGY; MOLECULAR CONVERGENCE; MUTATIONAL ANALYSIS; NOD2 GENE; NOD52 GENE; OXIDATIVE STRESS; PRIORITY JOURNAL; RISK ASSESSMENT; SIMULATION; STOCHASTIC PETRI NET SIMULATION; ULK1 GENE; VALIDATION PROCESS; COMPLICATION; GENETICS; MUTATION; PHENOTYPE;

AUTISM SPECTRUM DISORDER; AUTOPHAGY; COMORBIDITY; HUMANS; INFLAMMATORY BOWEL DISEASES; MUTATION; PHENOTYPE;

EID: 84988355124     PISSN: 15320464     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jbi.2016.08.008     Document Type: Article

References (73)

1. [1] Melamed, R.D., Emmett, K.J., Madubata, C., Rzhetsky, A., Rabadan, R., Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes. Nat. Commun., 6, 2015, 7033, 10.1038/ncomms8033.
2. [2] Park, J., Lee, D.-S., Christakis, N.A., Barabási, A.-L., The impact of cellular networks on disease comorbidity. Mol. Syst. Biol., 5, 2009, 262, 10.1038/msb.2009.16.
3. [3] Menche, J., Sharma, A., Kitsak, M., et al. Disease networks. Uncovering disease-disease relationships through the incomplete interactome. Science, 347(6224), 2015, 1257601, 10.1126/science.125760.
4. [4] Blätke, M.A., Heiner, M., Marwan, W., BioModel Engineering with Petri Nets. Robeva, R., (eds.) Algebraic and Discrete Mathematical Methods for Modern Biology, 2015, Elsevier Inc., 141–193.
5. [5] Peleg, M., Rubin, D., Altman, R.B., Using Petri Net tools to study properties and dynamics of biological systems. J. Am. Med. Inform. Assoc. 12:2 (2005), 181–199, 10.1197/jamia.M1637.
6. [6] Koch, I., Reisig, W., Schreiber, F., Modeling in Systems Biology: The Petri Net Approach. first ed., 2011, Springer-Verlag New York, Inc., New York, NY, USA.
7. [7] Lee, K.-M., Hwang, S.-K., Lee, J.-A., Neuronal autophagy and neurodevelopmental disorders. Exp. Neurobiol. 22:3 (2013), 133–142, 10.5607/en.2013.22.3.133.
8. [8] Feng, Y., He, D., Yao, Z., Klionsky, D.J., The machinery of macroautophagy. Cell Res. 24:1 (2014), 24–41, 10.1038/cr.2013.168.
9. [9] He, C., Klionsky, D.J., Regulation mechanisms and signaling pathways of autophagy. Ann. Rev. Genet. 43 (2009), 67–93, 10.1146/annurev-genet-102808-114910.
10. [10] Khaminets, A., Behl, C., Dikic, I., Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol. 26:1 (2015), 6–16, 10.1016/j.tcb.2015.08.010.
11. [11] Levine, B., Mizushima, N., Virgin, H., Autophagy in immunity and inflammation. Nature 469:7330 (2011), 323–335, 10.1038/nature09782.
12. [12] Mizushima, N., Levine, B., Cuervo, A.M., Klionsky, D.J., Autophagy fights disease through cellular self-digestion. Nature 451:7182 (2008), 1069–1075, 10.1038/nature06639.
13. [13] American Psychiatric Association. Diagnostic and statistical manual of mental disorders: (DSM-5®). American Psychiatric Pub, 2013. http://dx.doi.org/10.1176/appi.books.9780890425596.
14. [14] Elsabbagh, M., Divan, G., Koh, Y.-J., et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 5:3 (2012), 160–179, 10.1002/aur.239.
15. [15] Poultney, C.S., Goldberg, A.P., Drapeau, E., et al. Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder. Am. J. Hum. Genet. 93:4 (2013), 607–619, 10.1016/j.ajhg.2013.09.001.
16. [16] Huguet, G., Ey, E., Bourgeron, T., The genetic landscapes of autism spectrum disorders. Annu. Rev. Genomics Hum. Genet. 14 (2013), 191–213, 10.1146/annurev-genom-091212-153431.
17. [17] Abrahams, B.S., Geschwind, D.H., Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9:5 (2008), 341–355, 10.1038/nrg2346.
18. [18] Chang, J., Gilman, S.R., Chiang, A.H., Sanders, S.J., Vitkup, D., Genotype to phenotype relationships in autism spectrum disorders. Nat. Neurosci. 18:2 (2015), 191–198, 10.1038/nn.3907.
19. [19] Redon, R., Ishikawa, S., Fitch, K.R., et al. Global variation in copy number in the human genome. Nature 444:7118 (2006), 444–454, 10.1038/nature05329.
20. [20] Tang, G., Gudsnuk, K., Kuo, S.-H., et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83:5 (2014), 1131–1143, 10.1016/j.neuron.2014.07.040.
21. [21] Doshi-Velez, F., Ge, Y., Kohane, I., Comorbidity clusters in autism spectrum disorders: an electronic health record time-series analysis. Pediatrics 133:1 (2014), e54–e63, 10.1542/peds.2013-0819.
22. [22] Kohane, I.S., McMurry, A., Weber, G., et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One, 7(4), 2012, e33224, 10.1371/journal.pone.0033224.
23. [23] Horvath, K., Perman, J.A., Autistic disorder and gastrointestinal disease. Curr. Opin. Pediatr. 14:5 (2002), 583–587.
24. [24] Valicenti-McDermott, M., McVicar, K., Rapin, I., Wershil, B.K., Cohen, H., Shinnar, S., Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J. Dev. Behav. Pediatr. 27:2 suppl. (2006), S128–S136 (accessed June 22, 2015).
25. [25] Doshi-Velez, F., Avillach, P., Palmer, N., et al. Prevalence of inflammatory bowel disease among patients with autism spectrum disorders. Inflamm. Bowel Dis. 21:10 (2015), 2281–2288, 10.1097/MIB.0000000000000502.
26. [26] Gardet, A., Xavier, R.J., Common alleles that influence autophagy and the risk for inflammatory bowel disease. Curr. Opin. Immunol. 24:5 (2012), 522–529, 10.1016/j.coi.2012.08.001.
27. [27] Hoefkens, E., Nys, K., John, J.M., et al. Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress. Autophagy 9:12 (2013), 2046–2055, 10.4161/auto.26337.
28. [28] Franke, A., McGovern, D.P.B., Barrett, J.C., et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42:12 (2010), 1118–1125, 10.1038/ng.717.
29. [29] Barrett, J.C., Hansoul, S., Nicolae, D.L., et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40:8 (2008), 955–962, 10.1038/ng.175.
30. [30] Rioux, J.D., Xavier, R.J., Taylor, K.D., et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39:5 (2007), 596–604, 10.1038/ng2032.
31. [31] Hampe, J., Franke, A., Rosenstiel, P., et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39:2 (2006), 207–211, 10.1038/ng1954.
32. [32] Parkes, M., Barrett, J.C., Prescott, N.J., et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39:7 (2007), 830–832, 10.1038/ng2061.
33. [33] McCarroll, S.A., Huett, A., Kuballa, P., et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat. Genet. 40:9 (2008), 1107–1112, 10.1038/ng.215.
34. [34] Henckaerts, L., Cleynen, I., Brinar, M., et al. Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease. Inflamm. Bowel Dis. 17:6 (2011), 1392–1397, 10.1002/ibd.21486.
35. [35] Brinar, M., Vermeire, S., Cleynen, I., et al. Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn's disease patients. J. Crohns Colitis. 6:1 (2012), 43–50, 10.1016/j.crohns.2011.06.008.
36. [36] Till, A., Lipinski, S., Ellinghaus, D., et al. Autophagy receptor CALCOCO2/NDP52 takes center stage in Crohn disease. Autophagy 9:8 (2013), 1256–1257, 10.4161/auto.25483.
37. [37] Ellinghaus, D., Zhang, H., Zeissig, S., et al. Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies. Gastroenterology 145:2 (2013), 339–347, 10.1053/j.gastro.2013.04.040.
38. [38] Lassen, K.G., Kuballa, P., Conway, K.L., et al. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc. Natl. Acad. Sci. USA 111:21 (2014), 7741–7746, 10.1073/pnas.1407001111.
39. [39] Travassos, L.H., Carneiro, L.A.M., Ramjeet, M., et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11:1 (2010), 55–62, 10.1038/ni.1823.
40. [40] Xavier, R.J., Podolsky, D.K., Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:7152 (2007), 427–434, 10.1038/nature06005.
41. [41] Gillespie, D.T., Exact stochastic simulation of coupled chemical reactions. J. Phys. Chem. 81:25 (1977), 2340–2361, 10.1021/j100540a008.
42. [42] Chaouiya, C., Petri net modelling of biological networks. Brief Bioinform. 8:4 (2007), 210–219, 10.1093/bib/bbm029.
43. [43] Steggles, L.J., Banks, R., Shaw, O., Wipat, A., Qualitatively modelling and analysing genetic regulatory networks: a Petri net approach. Bioinformatics 23:3 (2007), 336–343, 10.1093/bioinformatics/btl596.
44. [44] Chauhan, S., Mandell, M.A., Deretic, V., IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol. Cell. 58:3 (2015), 507–521, 10.1016/j.molcel.2015.03.020.
45. [45] Le Grand, J.N., Chakrama, F.Z., Seguin-Py, S., et al. GABARAPL1 (GEC1): original or copycat?. Autophagy 7:10 (2011), 1098–1107, 10.4161/auto.7.10.15904.
46. [46] Rohr, C., Marwan, W., Heiner, M., Snoopy–a unifying Petri net framework to investigate biomolecular networks. Bioinformatics 26:7 (2010), 974–975, 10.1093/bioinformatics/btq050.
47. [47] Heiner, M., Koch, I., Will, J., Model validation of biological pathways using Petri nets–demonstrated for apoptosis. Biosystems 75:1–3 (2004), 15–28, 10.1016/j.biosystems.2004.03.003.
48. [48] Heiner, M., Schwarick, M., Wegener, J., Charlie – an extensible Petri net analysis tool. Proceedings of the PETRI NETS 2015 LNCS, vol. 9115, 2015, Springer, Brussels, 200–211.
49. [49] Russell, R.C., Tian, Y., Yuan, H., et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15:7 (2013), 741–750, 10.1038/ncb2757.
50. [50] Zalckvar, E., Berissi, H., Mizrachy, L., et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep. 10:3 (2009), 285–292, 10.1038/embor.2008.246.
51. [51] Zalckvar, E., Berissi, H., Eisenstein, M., Kimchi, A., Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-X L. Autophagy 5:5 (2014), 720–722, 10.4161/auto.5.5.8625.
52. [52] Maiuri, M.C., Le Toumelin, G., Criollo, A., et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J. 26:10 (2007), 2527–2539, 10.1038/sj.emboj.7601689.
53. [53] Pattingre, S., Tassa, A., Qu, X., et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:6 (2005), 927–939, 10.1016/j.cell.2005.07.002.
54. [54] Wong, P.-M., Puente, C., Ganley, I.G., Jiang, X., The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 9:2 (2013), 124–137, 10.4161/auto.23323.
55. [55] Wirth, M., Joachim, J., Tooze, S.A., Autophagosome formation–the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage. Semin. Cancer Biol. 23:5 (2013), 301–309, 10.1016/j.semcancer.2013.05.007.
56. [56] Geng, J., Klionsky, D.J., The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. “Protein modifications: beyond the usual suspects” review series. EMBO Rep. 9:9 (2008), 859–864, 10.1038/embor.2008.163.
57. [57] Weidberg, H., Shpilka, T., Shvets, E., Elazar, Z., Mammalian Atg8s: one is simply not enough. Autophagy 6:6 (2010), 808–809, 10.1038/emboj.2010.74.
58. [58] Moreau, K., Renna, M., Rubinsztein, D.C., Connections between SNAREs and autophagy. Trends Biochem. Sci. 38:2 (2013), 57–63, 10.1016/j.tibs.2012.11.004.
59. [59] Verlhac, P., Grégoire, I.P., Azocar, O., et al. Autophagy receptor NDP52 regulates pathogen-containing autophagosome maturation. Cell Host Microbe. 17:4 (2015), 515–525, 10.1016/j.chom.2015.02.008.
60. [60] Komatsu, M., Waguri, S., Ueno, T., et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169:3 (2005), 425–434, 10.1083/jcb.200412022.
61. [61] Saitoh, T., Fujita, N., Jang, M.H., et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456:7219 (2008), 264–268, 10.1038/nature07383.
62. [62] Thurston, T.L.M., Ryzhakov, G., Bloor, S., von Muhlinen, N., Randow, F., The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immunol. 10:11 (2009), 1215–1221, 10.1038/ni.1800.
63. [63] Cooney, R., Baker, J., Brain, O., et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16:1 (2010), 90–97, 10.1038/nm.2069.
64. [64] Kim, J., Kundu, M., Viollet, B., Guan, K.-L., AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13:2 (2011), 132–141, 10.1038/ncb2152.
65. [65] Lee, E.-J., Tournier, C., The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy. Autophagy 7:7 (2011), 689–695, 10.4161/auto.7.7.15450.
66. [66] Velikkakath, A.K.G., Nishimura, T., Oita, E., Ishihara, N., Mizushima, N., Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. Mol. Biol. Cell. 23:5 (2012), 896–909, 10.1091/mbc.E11-09-0785.
67. [67] Itakura, E., Mizushima, N., Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6:6 (2010), 764–776, 10.4161/auto.6.6.12709.
68. [68] Kabeya, Y., Mizushima, N., Yamamoto, A., Oshitani-Okamoto, S., Ohsumi, Y., Yoshimori, T., LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J. Cell Sci. 117:Pt 13 (2004), 2805–2812, 10.1242/jcs.01131.
69. [69] Wittkopf, N., Günther, C., Martini, E., et al. Lack of intestinal epithelial atg7 affects paneth cell granule formation but does not compromise immune homeostasis in the gut. Clin. Dev. Immunol., 2012, 2012, 278059, 10.1155/2012/278059.
70. [70] Inoue, J., Nishiumi, S., Fujishima, Y., et al. Autophagy in the intestinal epithelium regulates Citrobacter rodentium infection. Arch. Biochem. Biophys. 521:1–2 (2012), 95–101, 10.1016/j.abb.2012.03.019.
71. [71] Hucka, M., Finney, A., Sauro, H.M., et al. The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19:4 (2003), 524–531, 10.1093/bioinformatics/btg015.
72. [72] Cadwell, K., Patel, K.K., Maloney, N.S., et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141:7 (2010), 1135–1145, 10.1016/j.cell.2010.05.009.
73. [73] Li, Q., Zhou, J.-M., The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder. Neuroscience 324 (2016), 131–139, 10.1016/j.neuroscience.2016.03.013.