Abstract
Vitamin D receptor (VDR) signaling has been found to contribute to the pathology of numerous neuropsychiatric diseases including schizophrenia. Notably, VDR signaling has a functional relationship with many long non-coding RNAs (lncRNAs) such as SNHG6, LINC00346 and LINC00511. We calculated expression of these lncRNAs in the venous blood of patients with schizophrenia versus healthy individuals. Expression of SNHG6 was significantly higher in cases versus controls (posterior beta = 0.552, adjusted P value < 0.0001). This pattern of expression was detected in both men (posterior beta = 0.556, adjusted P value < 0.0001) and women (posterior beta = 0.31, adjusted P value = 0.005). Expression of LINC00346 was also higher in cases versus controls (posterior beta = 0.497, adjusted P value < 0.0001) and in distinct sex-based comparisons (posterior beta = 0.451, adjusted P value = 0.009 among men and posterior beta = 0.214, P value = 0.004 among women). Expression of LINC00511 was higher in cases versus controls (posterior beta = 0.318, adjusted P value = 0.01). While sex-based comparisons revealed significant difference in expression of LINC00511 among female subgroups (posterior beta = 0.424, adjusted P value = 0.016), such comparison showed no difference among male cases and male controls (adjusted P value = 0.295). The expression levels of SNHG6 distinguished patients with schizophrenia from controls, with AUC = 0.932. LINC00346 and LINC00511 distinguished between the two groups with AUC values of 0.795 and 0.706, respectively. Therefore, these lncRNAs might be used as markers for schizophrenia.
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The analyzed data sets generated during the study are available from the corresponding author on reasonable request.
References
Asadzadeh Manjili F, Kalantar SM, Arsang-Jang S, Ghafouri-Fard S, Taheri M, Sayad A (2018) Upregulation of vitamin D-related genes in schizophrenic patients. Neuropsychiatr Dis Treat 14:2583–2591
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders. https://doi.org/10.1176/appi.books.9780890425596
Beveridge NJ, Gardiner E, Carroll A, Tooney P, Cairns M (2010) Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 15:1176–1189
Bhugra D (2005) The global prevalence of schizophrenia. PLoS Med 2:e151–e175
Bikle DD (2021) Vitamin D regulation of and by long non coding RNAs. Mol Cell Endocrinol 532 111317
Børglum AD, Demontis D, Grove J, Pallesen J, Hollegaard MV, Pedersen C, Hedemand A, Mattheisen M, Uitterlinden A, Nyegaard M (2014) Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci. Mol Psychiatry 19:325–333
Carlberg C (2014) Genome-wide (over) view on the actions of vitamin D. Front Physiol 5:167
Chang L, Yuan Y, Li C, Guo T, Qi H, Xiao Y, Dong X, Liu Z, Liu Q (2016) Upregulation of SNHG6 regulates ZEB1 expression by competitively binding miR-101-3p and interacting with UPF1 in hepatocellular carcinoma. Cancer Lett 383:183–194
Cui X, Mcgrath JJ, Burne TH, Eyles DW (2021) Vitamin D and schizophrenia: 20 years on. Mol Psychiatry 1–13
Cui X, Pelekanos M, Liu P-Y, Burne T, McGrath J, Eyles D (2013) The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain. Neuroscience 236:77–87
Cui Z, Pu T, Zhang Y, Wang J, Zhao Y (2020) Long non-coding RNA LINC00346 contributes to cisplatin resistance in nasopharyngeal carcinoma by repressing miR-342–5p. Open biol 10190286
Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F (2003) Vitamin D3 and brain development. Neuroscience 118:641–653
Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ (2005) Distribution of the vitamin D receptor and 1α-hydroxylase in human brain. J Chem Neuroanat 29:21–30
Feron F, Burne T, Brown J, Smith E, McGrath J, Mackay-Sim A, Eyles D (2005) Developmental Vitamin D3 deficiency alters the adult rat brain. Brain Res Bull 65:141–148
Ghafouri-Fard S, Eghtedarian R, Hussen BM, Motevaseli E, Arsang-Jang S, Taheri M (2021a) Expression Analysis of VDR-Related LncRNAs in Autism Spectrum Disorder. J Mol Neurosci 71:1403–1409
Ghafouri-Fard S, Eghtedarian R, Taheri M, Beatrix Brhul A, Sadeghi-Bahmani D, Brand S (2021b) A Review on the Expression Pattern of Non-coding RNAs in Patients With Schizophrenia: With a Special Focus on Peripheral Blood as a Source of Expression Analysis. Front Psychiatry 12:640463
Gibbons A, Udawela M, Dean B (2018) Non-Coding RNA as Novel Players in the Pathophysiology of Schizophrenia. Non-Coding RNA 4:11
Harrison RN, Murray RM, Lee SH, Paya Cano J, Dempster D, Curtis CJ, Dima D, Gaughran F, Breen G, De Jong S (2016) Gene-expression analysis of clozapine treatment in whole blood of patients with psychosis. Psychiatr Genet 26:211–217
Jiang YJ, Bikle DD (2014) LncRNA: a new player in 1α, 25(OH)(2) vitamin D(3) /VDR protection against skin cancer formation. Exp Dermatol 23:147–150
Kholghi Oskooei V, Geranpayeh L, Omrani MD, Ghafouri-fard S (2018) Assessment of functional variants and expression of long noncoding RNAs in vitamin D receptor signaling in breast cancer. Cancer Manag Res 10:3451–3462
Li T, Wang B, Zhang L, Cui M, Sun B (2020) Silencing of long noncoding RNA LINC00346 inhibits the tumorigenesis of colorectal cancer through targeting MicroRNA-148b. Onco Targets Ther 13:3247
Mazdeh M, Zamani M, Eftekharian MM, Komaki A, Arsang-Jang S, Taheri M, Ghafouri-Fard S (2019) Expression analysis of vitamin D receptor-associated lncRNAs in epileptic patients. Metab Brain Dis 34:1457–1465
Mcgrath J (1999) Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia?. Schizophr Res 40:173–177
Mcgrath J, Iwazaki T, Eyles D, Burne T, Cui X, Ko P, Matsumoto I (2008) Protein expression in the nucleus accumbens of rats exposed to developmental vitamin D deficiency. PLoS One 3:e2383
Miyoshi T, Maruhashi M, van de Putte T, Kondoh H, Huylebroeck D, Higashi Y (2006) Complementary expression pattern of Zfhx1 genes Sip1 and deltaEF1 in the mouse embryo and their genetic interaction revealed by compound mutants. Dev Dyn 235:1941–1952
Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J, Hammond SM (2007) microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 8:1–11
Ravanpay AC, Hansen SJ, Olson JM (2010) Transcriptional inhibition of REST by NeuroD2 during neuronal differentiation. Mol Cell Neurosci 44:178–189
Ryan JW, Anderson PH, Morris HA (2015) Pleiotropic activities of vitamin D receptors–adequate activation for multiple health outcomes. Clin Biochem Rev 36:53
Schoenrock SA, Tarantino LM (2016) Developmental vitamin D deficiency and schizophrenia: the role of animal models. Genes Brain Behav 15:45–61
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59:22–33
Tong WH, Mu JF, Zhang SP (2020) LINC00346 accelerates the malignant progression of colorectal cancer via competitively binding to miRNA-101-5p/MMP9. Eur Rev Med Pharmacol Sci 24:6639–6646
Van Den Berg M, Krauskopf J, Ramaekers J, Kleinjans J, Prickaerts J, Briede J (2020) Circulating microRNAs as potential biomarkers for psychiatric and neurodegenerative disorders. Prog neurobiol 185 101732
Xu TP, Ma P, Wang WY, Shuai Y, Wang YF, Yu T, Xia R, Shu YQ (2019) KLF5 and MYC modulated LINC00346 contributes to gastric cancer progression through acting as a competing endogeous RNA and indicates poor outcome. Cell Death Differ 26:2179–2193
Zhao X, Liu Y, Li Z, Zheng S, Wang Z, Li W, Bi Z, Li L, Jiang Y, Luo Y, Lin Q, Fu Z, Rufu C (2018) Linc00511 acts as a competing endogenous RNA to regulate VEGFA expression through sponging hsa-miR-29b-3p in pancreatic ductal adenocarcinoma. J Cell Mol Med 22:655–667
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This study was financially supported by a grant from the Medical School of Shahid Beheshti University of Medical Sciences.
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MT and SGF wrote the manuscript and revised it. RE and FP supervised the study and performed the experiment. SAJ analyzed the data. MS was the clinical consultant and assessed patients for inclusion in the study. All authors approved the manuscript.
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Ghafouri-Fard, S., Eghtedarian, R., Seyedi, M. et al. Upregulation of VDR-associated lncRNAs in Schizophrenia. J Mol Neurosci 72, 239–245 (2022). https://doi.org/10.1007/s12031-021-01901-y
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DOI: https://doi.org/10.1007/s12031-021-01901-y