BACKGROUND: While hundreds of genes have been implicated already in the etiology of schizophrenia, the exact cause is not known or the disease is considered multigenic in origin. Recent discoveries of new types of RNAs and the gradual elimination of the "junk DNA" hypothesis refocused the attention on the noncoding part of the human genome. Here we re-analyzed a recent dataset of differentially methylated genes from schizophrenic patients and cross-tabulated them with cis regulatory and repetitive elements and microRNAs known to be involved in schizophrenia. RESULTS: We found that the number of schizophrenia-related (SZ) microRNA targets follows a scale-free distribution with several microRNA hubs and that schizophrenia-related microRNAs with shared targets form a small-world network. The top ten microRNAs with the highest number of SZ gene targets regulate approximately 80 % of all microRNA-regulated genes whereas the top two microRNAs regulate 40-52 % of all such genes. We also found that genes that are regulated by the same microRNAs tend to have more protein-protein interactions than randomly selected schizophrenia genes. This highlights the role microRNAs possibly play in coordinating the abundance of interacting proteins, an important function that has not been sufficiently explored before. The analysis revealed that GABBR1 is regulated by both of the top two microRNAs and acts as a hub by interacting with many schizophrenia-related genes and sharing several types of transcription-binding sites with its interactors. We also found that differentially methylated repetitive elements are significantly more methylated in schizophrenia, pointing out their potential role in the disease. CONCLUSIONS: We find that GABBR1 has a central importance in schizophrenia, even if no direct cause and effect have been shown for it for the time. In addition to being a hub in microRNA-derived regulatory pathways and protein-protein interactions, its centrality is also supported by the high number of cis regulatory elements and transcription factor-binding sites that regulate its transcription. These findings are in line with several genome-wide association studies that repeatedly find the major histocompatibility region (where GABBR1 is located) to have the highest number of single nucleotide polymorphisms in schizophrenics. Our model also offers an explanation for the downregulation of protein kinase B, another consistent finding in schizophrenic patients. Our observations support the notion that microRNAs fine-tune the amount of proteins acting in the same biological pathways in schizophrenia, giving further support to the emerging theory of competing endogenous RNAs.

CEITEC Central European Institute of Technology Masaryk University Kamenice 5 62500 Brno Czech Republic

Zobrazit více v PubMed

Kraepelin E. Dementia praecox and paraphrenia. [Chicago]: Chicago Medical Book Co; 1919.

Zhang F, Xu Y, Shugart YY, Yue W, Qi G, Yuan G, et al. Converging Evidence Implicates the Abnormal MicroRNA System in Schizophrenia. Schizophr Bull. 2015;41(3):728–35. doi: 10.1093/schbul/sbu148. PubMed DOI PMC

Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45(10):1150–9. doi: 10.1038/ng.2742. PubMed DOI PMC

Beveridge NJ, Cairns MJ. MicroRNA dysregulation in schizophrenia. Neurobiol Dis. 2012;46(2):263–71. doi: 10.1016/j.nbd.2011.12.029. PubMed DOI

Castellani CA, Laufer BI, Melka MG, Diehl EJ, O’Reilly RL, Singh SM. DNA methylation differences in monozygotic twin pairs discordant for schizophrenia identifies psychosis related genes and networks. BMC Med Genomics. 2015;8(1):17. doi: 10.1186/s12920-015-0093-1. PubMed DOI PMC

Wockner LF, Noble EP, Lawford BR, Young RM, Morris CP, Whitehall VL, et al. Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Transl. Psychiatry. 2014;4 doi: 10.1038/tp.2013.111. PubMed DOI PMC

Safran M, Dalah I, Alexander J, Rosen N, Iny Stein T, Shmoish M, et al. GeneCards Version 3: the human gene integrator. Database. 2010;2010:baq020. doi: 10.1093/database/baq020. PubMed DOI PMC

Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2013;41(Database issue):D808–15. doi: 10.1093/nar/gks1094. PubMed DOI PMC

Hegyi H. GABBR1 has a HERV-W LTR in its regulatory region--a possible implication for schizophrenia. Biol Direct. 2013;8:5. doi: 10.1186/1745-6150-8-5. PubMed DOI PMC

Banigan MG, Kao PF, Kozubek JA, Winslow AR, Medina J, Costa J, et al. Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One. 2013;8(1) doi: 10.1371/journal.pone.0048814. PubMed DOI PMC

Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ. Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry. 2010;15(12):1176–89. doi: 10.1038/mp.2009.84. PubMed DOI PMC

Gardiner E, Beveridge NJ, Wu JQ, Carr V, Scott RJ, Tooney PA, et al. Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells. Mol Psychiatry. 2012;17(8):827–40. doi: 10.1038/mp.2011.78. PubMed DOI PMC

Hansen T, Olsen L, Lindow M, Jakobsen KD, Ullum H, Jonsson E, et al. Brain expressed microRNAs implicated in schizophrenia etiology. PLoS One. 2007;2(9) doi: 10.1371/journal.pone.0000873. PubMed DOI PMC

Lai CY, Yu SL, Hsieh MH, Chen CH, Chen HY, Wen CC, et al. MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia. PLoS One. 2011;6(6) doi: 10.1371/journal.pone.0021635. PubMed DOI PMC

Moreau MP, Bruse SE, David-Rus R, Buyske S, Brzustowicz LM. Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder. Biol Psychiatry. 2011;69(2):188–93. doi: 10.1016/j.biopsych.2010.09.039. PubMed DOI PMC

Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, et al. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007;8(2):R27. doi: 10.1186/gb-2007-8-2-r27. PubMed DOI PMC

Pietersen CY, Mauney SA, Kim SS, Lim MP, Rooney RJ, Goldstein JM, et al. Molecular profiles of pyramidal neurons in the superior temporal cortex in schizophrenia. J Neurogenet. 2014;28(1–2):53–69. doi: 10.3109/01677063.2014.882918. PubMed DOI PMC

Santarelli DM, Beveridge NJ, Tooney PA, Cairns MJ. Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia. Biol Psychiatry. 2011;69(2):180–7. doi: 10.1016/j.biopsych.2010.09.030. PubMed DOI

Schizophrenia Psychiatric Genome-Wide Association Study C Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43(10):969–76. doi: 10.1038/ng.940. PubMed DOI PMC

Smalheiser NR, Lugli G, Zhang H, Rizavi H, Cook EH, Dwivedi Y. Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects. PLoS One. 2014;9(1) doi: 10.1371/journal.pone.0086469. PubMed DOI PMC

Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008;40(6):751–60. doi: 10.1038/ng.138. PubMed DOI

Tabares-Seisdedos R, Rubenstein JL. Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. Mol Psychiatry. 2009;14(6):563–89. doi: 10.1038/mp.2009.2. PubMed DOI

Xu Y, Li F, Zhang B, Zhang K, Zhang F, Huang X, et al. MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia. Schizophr Res. 2010;119(1–3):219–27. doi: 10.1016/j.schres.2010.02.1070. PubMed DOI

Zhu Y, Kalbfleisch T, Brennan MD, Li Y. A MicroRNA gene is hosted in an intron of a schizophrenia-susceptibility gene. Schizophr Res. 2009;109(1–3):86–9. doi: 10.1016/j.schres.2009.01.022. PubMed DOI PMC

Feng J, Sun G, Yan J, Noltner K, Li W, Buzin CH, et al. Evidence for X-chromosomal schizophrenia associated with microRNA alterations. PLoS One. 2009;4(7) doi: 10.1371/journal.pone.0006121. PubMed DOI PMC

Kim AH, Reimers M, Maher B, Williamson V, McMichael O, McClay JL, et al. MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders. Schizophr Res. 2010;124(1–3):183–91. doi: 10.1016/j.schres.2010.07.002. PubMed DOI PMC

Hsu SD, Tseng YT, Shrestha S, Lin YL, Khaleel A, Chou CH, et al. miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions. Nucleic Acids Res. 2014;42(Database issue):D78–85. doi: 10.1093/nar/gkt1266. PubMed DOI PMC

Rappaport N, Twik M, Nativ N, Stelzer G, Bahir I, Stein TI, et al. MalaCards: A Comprehensive Automatically-Mined Database of Human Diseases. Curr Protoc Bioinformatics. 2014;47:1 24 1–1 19. doi: 10.1002/0471250953.bi0124s47. PubMed DOI

Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2014;42(Database issue):D68–73. doi: 10.1093/nar/gkt1181. PubMed DOI PMC

Clauset A, Shalizi CR, Newman ME. Power-law distributions in empirical data. SIAM review. 2009;51(4):661–703. doi: 10.1137/070710111. DOI

Gillespie CS. Fitting heavy tailed distributions: the poweRlaw package. arXiv preprint arXiv:1407.3492. 2014.

Montoya JM, Sol RV. Small world patterns in food webs. J Theor Biol. 2002;214(3):405–12. doi: 10.1006/jtbi.2001.2460. PubMed DOI

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504. doi: 10.1101/gr.1239303. PubMed DOI PMC

Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215(3):403–10. doi: 10.1016/S0022-2836(05)80360-2. PubMed DOI

Jurka J, Kapitonov VV, Pavlicek A, Klonowski P, Kohany O, Walichiewicz J. Repbase Update, a database of eukaryotic repetitive elements. Cytogenet Genome Res. 2005;110(1–4):462–7. doi: 10.1159/000084979. PubMed DOI

Caputo V, Ciolfi A, Macri S, Pizzuti A. The emerging role of MicroRNA in schizophrenia. CNS Neurol Disord Drug Targets. 2015;14(2):208–21. doi: 10.2174/1871527314666150116124253. PubMed DOI

Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010;466(7308):835–40. doi: 10.1038/nature09267. PubMed DOI PMC

Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet. 2004;36(2):131–7. doi: 10.1038/ng1296. PubMed DOI

Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505(7483):344–52. doi: 10.1038/nature12986. PubMed DOI PMC

Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, et al. The accessible chromatin landscape of the human genome. Nature. 2012;489(7414):75–82. doi: 10.1038/nature11232. PubMed DOI PMC

Kheradpour P, Kellis M. Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 2014;42(5):2976–87. doi: 10.1093/nar/gkt1249. PubMed DOI PMC

Leboyer M, Tamouza R, Charron D, Faucard R, Perron H. Human endogenous retrovirus type W (HERV-W) in schizophrenia: a new avenue of research at the gene-environment interface. World J Biol Psychiatry. 2013;14(2):80–90. doi: 10.3109/15622975.2010.601760. PubMed DOI

Fatemi SH, Folsom TD, Thuras PD. Deficits in GABA(B) receptor system in schizophrenia and mood disorders: a postmortem study. Schizophr Res. 2011;128(1–3):37–43. doi: 10.1016/j.schres.2010.12.025. PubMed DOI PMC

Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S, et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology. 2012;62(3):1574–83. doi: 10.1016/j.neuropharm.2011.01.022. PubMed DOI PMC

De Luca V, Muglia P, Masellis M, Jane Dalton E, Wong GW, Kennedy JL. Polymorphisms in glutamate decarboxylase genes: analysis in schizophrenia. Psychiatr Genet. 2004;14(1):39–42. doi: 10.1097/00041444-200403000-00006. PubMed DOI

Rudolph U, Mohler H. GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annu Rev Pharmacol Toxicol. 2014;54:483–507. doi: 10.1146/annurev-pharmtox-011613-135947. PubMed DOI PMC

Bandyopadhyay S, Bhattacharyya M. PuTmiR: a database for extracting neighboring transcription factors of human microRNAs. BMC Bioinformatics. 2010;11:190. doi: 10.1186/1471-2105-11-190. PubMed DOI PMC

Schmeier S, Schaefer U, Essack M, Bajic VB. Network analysis of microRNAs and their regulation in human ovarian cancer. BMC Syst Biol. 2011;5:183. doi: 10.1186/1752-0509-5-183. PubMed DOI PMC

Balu DT, Carlson GC, Talbot K, Kazi H, Hill-Smith TE, Easton RM, et al. Akt1 deficiency in schizophrenia and impairment of hippocampal plasticity and function. Hippocampus. 2012;22(2):230–40. doi: 10.1002/hipo.20887. PubMed DOI PMC

Lu FF, Su P, Liu F, Daskalakis ZJ. Activation of GABA(B) receptors inhibits protein kinase B/glycogen synthase kinase 3 signaling. Mol Brain. 2012;5:41. doi: 10.1186/1756-6606-5-41. PubMed DOI PMC

van Beveren NJ, Buitendijk GH, Swagemakers S, Krab LC, Roder C, de Haan L, et al. Marked reduction of AKT1 expression and deregulation of AKT1-associated pathways in peripheral blood mononuclear cells of schizophrenia patients. PLoS One. 2012;7(2) doi: 10.1371/journal.pone.0032618. PubMed DOI PMC

Guo AY, Sun J, Jia P, Zhao Z. A novel microRNA and transcription factor mediated regulatory network in schizophrenia. BMC Syst Biol. 2010;4:10. doi: 10.1186/1752-0509-4-10. PubMed DOI PMC

Liang H, Li WH. MicroRNA regulation of human protein protein interaction network. RNA. 2007;13(9):1402–8. doi: 10.1261/rna.634607. PubMed DOI PMC

Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011;146(3):353–8. doi: 10.1016/j.cell.2011.07.014. PubMed DOI PMC

Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich gene expression hubs