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Original Research | Open Access

Expression analysis of microRNAs as candidate biomarkers in Iranian children with autism spectrum disorder

Maryam Rahnamaa,b( )Hossein Abdul-TehraniaMohammad Reza MohammadicMehdi MirzaiedPardis Jahandideha,bAmirhossein Memarib
Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 331-14115, Iran
Sports Medicine Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran 14117-34141, Iran
Psychiatry and Psychology Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran 13337-14914, Iran
Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki P.O. BOX 63 00014, Finland
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Abstract

Background

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Despite its biological underpinnings, ASD is yet diagnosed based on behavioral assessments. The importance of early ASD detection is supported by a large body of evidence. Early diagnosis can facilitate more effective interventions, reducing the socioeconomic costs and improving the quality of life of both children with ASD and their families. This study aims to investigate the expression patterns of ASD-related microRNAs (miRNAs) in Iranian children with ASD compared with matched neurotypical controls, to identify candidate miRNA biomarkers.

Method

Validation of ASD-related miRNAs was performed using the qRT-PCR method in plasma samples from 20 ASD and 20 unaffected individuals. Differentially expressed miRNAs were identified based on relative quantification analysis. Then, the diagnostic potential of each candidate miRNA was assessed using receiver operating characteristics (ROC) curve analysis.

Results

Based on statistical and bioinformatics analyses, eight miRNAs were recommended as candidate biomarkers. Furthermore, differential expression of five of these miRNAs—miR-146a-5p, miR-338-3p, miR-181b-5p, let-7a-5p, and miR-140-3p—was confirmed experimentally by qRT-PCR (p-value < 0.05) based on a t-test. miR-140-3p was not further detected as significant by the Mann–Whitney test. The sensitivity, specificity, and area under the ROC curve were calculated for each validated miRNA and fell in the ranges of 75%–91%, 66.67%–83.33%, and 74%–90%, respectively.

Conclusions

This study revealed a panel of high-confidence differentially expressed miRNAs, which requires further investigation in larger sample sizes and by other validation tests. These findings could be a step forward in the field of ASD biomarker discovery.

Electronic Supplementary Material

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jnrt-12-1-100096_ESM.docx (1.4 MB)

References

1

Hirota T, King BH. Autism spectrum disorder: a review. JAMA. 2023;329(2): 157–168. https://doi.org/10.1001/jama.2022.23661.

2

Salari N, Rasoulpoor S, Rasoulpoor S, et al. The global prevalence of autism spectrum disorder: a comprehensive systematic review and meta-analysis. Ital J Pediatr. 2022;48(1):112. https://doi.org/10.1186/s13052-022-01310-w.

3

Knopf A. Autism prevalence increases from 1 in 60 to 1 in 54: CDC. Brown Univ Child Adolesc Behav Lett. 2020;36(6):4. https://doi.org/10.1002/cbl.30470.

4

Li Z, Yang LJ, Chen H, et al. Global, regional and national burden of autism spectrum disorder from 1990 to 2019: results from the Global Burden of Disease Study 2019. Epidemiol Psychiatr Sci. 2022;31:e33. https://doi.org/10.1017/S2045796022000178.

5

Mohammadi MR, Ahmadi N, Khaleghi A, et al. Prevalence of autism and its comorbidities and the relationship with maternal psychopathology: a national population-based study. Arch Iran Med. 2019;22(10):546–553.

6

Chaste P, Leboyer M. Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci. 2012;14(3):281–292. https://doi.org/10.31887/DCNS.2012.14.3/pchaste.

7

Keil-Stietz K, Lein PJ. Gene × environment interactions in autism spectrum disorders. Curr Top Dev Biol. 2023;152:221–284. https://doi.org/10.1016/bs.ctdb.2022.11.001.

8

Khogeer AA, AboMansour IS, Mohammed DA. The role of genetics, epigenetics, and the environment in ASD: a mini review. Epigenomes. 2022;6(2):15. https://doi.org/10.3390/epigenomes6020015.

9

Yoon SH, Choi J, Lee WJ, et al. Genetic and epigenetic etiology underlying autism spectrum disorder. J Clin Med. 2020;9(4):966. https://doi.org/10.3390/jcm9040966.

10

Gabbay-Dizdar N, Ilan M, Meiri G, et al. Early diagnosis of autism in the community is associated with marked improvement in social symptoms within 1–2 years. Autism. 2022;26(6):1353–1363. https://doi.org/10.1177/13623613211049011.

11

Sheldrick RC, Carter AS, Eisenhower A, et al. Effectiveness of screening in early intervention settings to improve diagnosis of autism and reduce health disparities. JAMA Pediatr. 2022;176(3):262–269. https://doi.org/10.1001/jamapediatrics.2021.5380.

12

Becerra MA. Closing the diagnostic gap: early autism spectrum disorder screening for every child. Health Soc Work. 2022;47(2):87–91. https://doi.org/10.1093/hsw/hlac008.

13

Fuller EA, Kaiser AP. The effects of early intervention on social communication outcomes for children with autism spectrum disorder: a meta-analysis. J Autism Dev Disord. 2020;50(5):1683–1700. https://doi.org/10.1007/s10803-019-03927-z.

14

Liu XK, Lin J, Zhang HJ, et al. Oxidative stress in autism spectrum disorder-current progress of mechanisms and biomarkers. Front Psychiatr. 2022;13:813304. https://doi.org/10.3389/fpsyt.2022.813304.

15

Jensen AR, Lane AL, Werner BA, et al. Modern biomarkers for autism spectrum disorder: future directions. Mol Diagn Ther. 2022;26(5):483–495. https://doi.org/10.1007/s40291-022-00600-7.

16

Yao F, Zhang KY, Feng CY, et al. Protein biomarkers of autism spectrum disorder identified by computational and experimental methods. Front Psychiatr. 2021;12:554621. https://doi.org/10.3389/fpsyt.2021.554621.

17

Hiremath CS, Sagar KJV, Yamini BK, et al. Emerging behavioral and neuroimaging biomarkers for early and accurate characterization of autism spectrum disorders: a systematic review. Transl Psychiatry. 2021;11(1):42. https://doi.org/10.1038/s41398-020-01178-6.

18

Salloum-Asfar S, Satheesh NJ, Abdulla SA. Circulating miRNAs, small but promising biomarkers for autism spectrum disorder. Front Mol Neurosci. 2019;12:253. https://doi.org/10.3389/fnmol.2019.00253.

19

Tsujimura K, Shiohama T, Takahashi E. MicroRNA biology on brain development and neuroimaging approach. Brain Sci. 2022;12(10):1366. https://doi.org/10.3390/brainsci12101366.

20

Kos MZ, Puppala S, Cruz D, et al. Blood-based miRNA biomarkers as correlates of brain-based miRNA expression. Front Mol Neurosci. 2022;15:817290. https://doi.org/10.3389/fnmol.2022.817290.

21

Adlakha YK, Saini N. Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Mol Cancer. 2014;13:33. https://doi.org/10.1186/1476-4598-13-33.

22

Jin XF, Wu N, Wang L, et al. Circulating microRNAs: a novel class of potential biomarkers for diagnosing and prognosing central nervous system diseases. Cell Mol Neurobiol. 2013;33(5):601–613. https://doi.org/10.1016/j.pneurobio.2019.101732.

23

Wang J, Chen JY, Sen S. MicroRNA as biomarkers and diagnostics. J Cell Physiol. 2016;231(1):25–30. https://doi.org/10.1002/jcp.25056.

24

Abu-Elneel K, Liu T, Gazzaniga FS, et al. Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics. 2008;9(3):153–161. https://doi.org/10.1007/s10048-008-0133-5.

25
Garrido-Torres N, Guzmán-Torres K, García-Cerro S, et al. miRNAs as biomarkers of autism spectrum disorder: a systematic review and meta-analysis. Eur Child Adolesc Psychiatr. 2023. https://doi.org/10.1007/s00787-023-02138-3. Feb 3.
26

Reay WR, Kiltschewskij DJ, Geaghan MP, et al. Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders. Sci Adv. 2022;8(14):eabj8969. https://doi.org/10.1126/sciadv.abj8969.

27

Ghahramani Seno MM, Hu PZ, Gwadry FG, et al. Gene and miRNA expression profiles in autism spectrum disorders. Brain Res. 2011;1380:85–97. https://doi.org/10.1016/j.brainres.2010.09.046.

28

Talebizadeh Z, Butler MG, Theodoro MF. Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism. Autism Res. 2008;1(4):240–250. https://doi.org/10.1002/aur.33.

29

Ozkul Y, Taheri S, Bayram KK, et al. A heritable profile of six miRNAs in autistic patients and mouse models. Sci Rep. 2020;10(1):9011. https://doi.org/10.1038/s41598-020-65847-8.

30

Shen L, Lin YX, Sun ZD, et al. Knowledge-guided bioinformatics model for identifying autism spectrum disorder diagnostic microRNA biomarkers. Sci Rep. 2016;6:39663. https://doi.org/10.1038/srep39663.

31

Gill PS, Dweep H, Rose S, et al. Integrated microRNA-mRNA expression profiling identifies novel targets and networks associated with autism. J Personalized Med. 2022;12(6):920. https://doi.org/10.3390/jpm12060920.

32

Maffioletti E, Cattaneo A, Rosso G, et al. Peripheral whole blood microRNA alterations in major depression and bipolar disorder. J Affect Disord. 2016;200: 250–258. https://doi.org/10.1016/j.jad.2016.04.021.

33

Wang LJ, Li SC, Kuo HC, et al. Gray matter volume and microRNA levels in patients with attention-deficit/hyperactivity disorder. Eur Arch Psychiatr Clin Neurosci. 2020;270(8):1037–1045. https://doi.org/10.1007/s00406-019-01032-x.

34

Liang CM, Mu YY, Tian H, et al. MicroRNA-140 silencing represses the incidence of Alzheimer's disease. Neurosci Lett. 2021;758:135674. https://doi.org/10.1016/j.neulet.2021.135674.

35

Cirnigliaro M, Barbagallo C, Gulisano M, et al. Expression and regulatory network analysis of miR-140-3p, a new potential serum biomarker for autism spectrum disorder. Front Mol Neurosci. 2017;10:250. https://doi.org/10.3389/fnmol.2017.00250.

36

Wang T, Pan M, Li W, Huang F, Liu X. Expression of miR-140-3p in children with autism spectrum disorders and its correlation with cyto-kines. Chin J Behav Med Brain Sci. 2019;28(5):416–420. https://doi.org/10.3760/cma.-j.issn.1674-6554.2019.05.007.

37
Cirnigliaro M. Profiling of Circulating microRNAs in Body Fluids from Autism Spectrum Disorder Patients. Website online:; 2019. http://dspace.unict.it/handle/10761/4129.
38

Wu ZG, Tan J, Lin LC, et al. MicroRNA-140-3p protects hippocampal neuron against pyroptosis to attenuate sevoflurane inhalation-induced post-operative cognitive dysfunction in rats via activation of HTR2A/ERK/Nrf2 axis by targeting DNMT1. Cell Death Dis. 2022;8(1):290. https://doi.org/10.1038/s41420-022-01068-4.

39

Nguyen LS, Lepleux M, Makhlouf M, et al. Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology. Mol Autism. 2016;7:1. https://doi.org/10.1186/s13229-015-0064-6.

40

Huang ZX, Chen YH, Guo HR, et al. Systematic review and bioinformatic analysis of microRNA expression in autism spectrum disorder identifies pathways associated with cancer, metabolism, cell signaling, and cell adhesion. Front Psychiatr. 2021;12:630876. https://doi.org/10.3389/fpsyt.2021.630876.

41

Jia YH, Wei YY. Modulators of microRNA function in the immune system. Int J Mol Sci. 2020;21(7):2357. https://doi.org/10.3390/ijms21072357.

42

Nguyen LS, Fregeac J, Bole-Feysot C, et al. Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders. Mol Autism. 2018;9:38. https://doi.org/10.1186/s13229-018-0219-3.

43

Fregeac J, Moriceau S, Poli A, et al. Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits. Mol Autism. 2020;11(1):22. https://doi.org/10.1186/s13229-020-00328-3.

44

Mundalil Vasu M, Anitha A, Thanseem I, et al. Serum microRNA profiles in children with autism. Mol Autism. 2014;5:40. https://doi.org/10.1186/2040-2392-5-40.

45

Wu XW, Li WR, Zheng Y. Recent progress on relevant microRNAs in autism spectrum disorders. Int J Mol Sci. 2020;21(16):5904. https://doi.org/10.3390/ijms21165904.

46

Indrieri A, Carrella S, Carotenuto P, et al. The pervasive role of the miR-181 family in development, neurodegeneration, and cancer. Int J Mol Sci. 2020;21(6):2092. https://doi.org/10.3390/ijms21062092.

47

Frye RE, Rose S, McCullough S, et al. MicroRNA expression profiles in autism spectrum disorder: role for miR-181 in immunomodulation. J Personalized Med. 2021;11(9):922. https://doi.org/10.3390/jpm11090922.

48

Li HW, Xu YR, Li WH, et al. Novel insights into the immune cell landscape and gene signatures in autism spectrum disorder by bioinformatics and clinical analysis. Front Immunol. 2023;13:1082950. https://doi.org/10.3389/fimmu.2022.1082950.

49

Rezaei T, Amini M, Hashemi ZS, et al. MicroRNA-181 serves as a dual-role regulator in the development of human cancers. Free Radic Biol Med. 2020;152:432–454. https://doi.org/10.1016/j.freeradbiomed.2019.12.043.

50

Sharma A, Mehan S. Targeting PI3K-AKT/mTOR signaling in the prevention of autism. Neurochem Int. 2021;147:105067. https://doi.org/10.1016/j.neuint.2021.105067.

51

Zhu J, Wang FL, Wang HB, et al. TNF-α mRNA is negatively regulated by microRNA-181a-5p in maturation of dendritic cells induced by high mobility group box-1 protein. Sci Rep. 2017;7(1):12239. https://doi.org/10.1038/s41598-017-12492-3.

52

Schumann CM, Sharp FR, Ander BP, et al. Possible sexually dimorphic role of miRNA and other sncRNA in ASD brain. Mol Autism. 2017;8:4. https://doi.org/10.1186/s13229-017-0117-0.

53

Qian Q, Zhang J, He FP, et al. Down-regulated expression of microRNA-338-5p contributes to neuropathology in Alzheimer's disease. Faseb J. 2019;33(3): 4404–4417. https://doi.org/10.1096/fj.201801846R.

54

Wu ZX, Cai ZX, Shi HS, et al. Effective biomarkers and therapeutic targets of nerve-immunity interaction in the treatment of depression: an integrated investigation of the miRNA-mRNA regulatory networks. Aging. 2022;14(8): 3569–3596. https://doi.org/10.18632/aging.204030.

55

Xie SS, Niu WX, Xu F, et al. Differential expression and significance of miRNAs in plasma extracellular vesicles of patients with Parkinson's disease. Int J Neurosci. 2022;132(7):673–688. https://doi.org/10.1080/00207454.2020.1835899.

56

Kos A, de Mooij-Malsen AJ, van Bokhoven H, et al. MicroRNA-338 modulates cortical neuronal placement and polarity. RNA Biol. 2017;14(7):905–913. https://doi.org/10.1080/15476286.2017.1325067.

57

Huang FZ, Long Z, Chen Z, et al. Investigation of gene regulatory networks associated with autism spectrum disorder based on MiRNA expression in China. PLoS One. 2015;10(6):e0129052. https://doi.org/10.1371/journal.pone.0129052.

58

Rosina E, Battan B, Siracusano M, et al. Disruption of mTOR and MAPK pathways correlates with severity in idiopathic autism. Transl Psychiatry. 2019;9(1):50. https://doi.org/10.1038/s41398-018-0335-z.

59

Rademacher S, Eickholt BJ. PTEN in autism and neurodevelopmental disorders. Cold Spring Harb Perspect Med. 2019;9(11):a036780. https://doi.org/10.1101/cshperspect.a036780.

60

Cao WL, Wang QP, Huang CJ. Let-7a inhibits tumor metastasis by regulating TGF-β/smad signaling in the colorectal adenocarcinoma cell line LS-174T. Anticancer Res. 2021;41(8):3801–3808. https://doi.org/10.21873/anticanres.15172.

61

Cao PF, Wang LX, Cheng Q, et al. Changes in serum miRNA-let-7 level in children with attention deficit hyperactivity disorder treated by repetitive transcranial magnetic stimulation or atomoxetine: an exploratory trial. Psychiatr Res. 2019;274:189–194. https://doi.org/10.1016/j.psychres.2019.02.037.

62

Tiberio P, Callari M, Angeloni V, et al. Challenges in using circulating miRNAs as cancer biomarkers. BioMed Res Int. 2015;2015:731479. https://doi.org/10.1155/2015/731479.

63

Pucchio A, Krance SH, Pur DR, et al. Artificial intelligence analysis of biofluid markers in age-related macular degeneration: a systematic review. Clin Ophthalmol. 2022;16:2463–2476. https://doi.org/10.2147/OPTH.S377262.

64

Roest HP, Ijzermans JNM, van der Laan LJW. Evaluation of RNA isolation methods for microRNA quantification in a range of clinical biofluids. BMC Biotechnol. 2021;21(1):48. https://doi.org/10.1186/s12896-021-00706-6.

65

Mestry C, Ashavaid TF, Shah SA. Key methodological challenges in detecting circulating miRNAs in different biofluids. Ann Clin Biochem. 2023;60(1):14–26. https://doi.org/10.1177/00045632221129778.

Journal of Neurorestoratology
Article number: 100096
Cite this article:
Rahnama M, Abdul-Tehrani H, Mohammadi MR, et al. Expression analysis of microRNAs as candidate biomarkers in Iranian children with autism spectrum disorder. Journal of Neurorestoratology, 2024, 12(1): 100096. https://doi.org/10.1016/j.jnrt.2024.100096

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Received: 19 July 2023
Revised: 24 December 2023
Accepted: 07 January 2024
Published: 26 January 2024
© 2024 The Authors.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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