Molecular Portrait of Potential Attention Deficit/ Hyperactivity Disorder Candidate Genes and Regulating Micrornas Expression in Normal Human Developing Brain Tissues
Main Article Content
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder in childhood affecting 5-6% of children, and is a major global health concern, which seems to increase in magnitude. The etiology of ADHD is still poorly understood, however; there are indications of genetic as well as environmental and epigenetic factors contributing to the development of the disorder. The objectives of this study was i) to identify potential ADHD candidate genes; ii) to explore spatial and temporal transcriptional fluctuation of the identified ADHD candidate genes in normal developing human brain tissues, and iii) to identify miRNAs regulating the identified ADHD candidate genes and explore how these miRNAs are expressed in normal developing human brain tissues.
From search in literature and publicly available databases, we identified 103 shared potential ADHD candidate genes. These genes were expressed and enriched in several human brain regions and developmental stages. Clustering analysis of these genes based on their expression levels showed a clear difference between fetal stage and the other developmental stages. There was no clear gender or brain region differences between samples. Further, functional analysis of these genes revealed that they participate in a variety of different and widely distributed functional pathways implicated with ADHD.
From miRNA-target prediction analysis, we identified twenty miRNAs regulating the identified 103 genes, and the expression pattern of these miRNAs was developmental stage dependent. These miRNAs were enriched in functional pathways and disease ontologies relevant to neurodevelopment.
The knowledge of the expression pattern of potential ADHD candidate genes and miRNAs, which regulate these genes across different stages of brain development, is essential for understanding normal brain development and subsequent disease development of the brain. In addition, identification of miRNA-regulated ADHD candidate genes can be used to develop blood-based molecular markers to be investigated in future studies of ADHD patients.
Keywords:
Attention-deficit/hyperactivity disorder, ADHD, microRNA, epigenetics, neurodevelopment, transcription
Article Details
How to Cite
DYPÅS, Lene B. et al.
Molecular Portrait of Potential Attention Deficit/ Hyperactivity Disorder Candidate Genes and Regulating Micrornas Expression in Normal Human Developing Brain Tissues.
Medical Research Archives, [S.l.], v. 8, n. 9, sep. 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2214>. Date accessed: 08 nov. 2024.
doi: https://doi.org/10.18103/mra.v8i9.2214.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. The American journal of psychiatry. 2007;164(6):942-8.
2. Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. Journal of child psychology and psychiatry, and allied disciplines. 2015;56(3):345-65.
3. Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics. 2015;135(4):e994-1001.
4. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author. http://dx.doi.org/10.1176/appi.books.9780890425596. American Psychiatric Association Publishing2013.
5. Biedermann F, Fleischhacker WW. Psychotic disorders in DSM-5 and ICD-11. CNS spectrums. 2016;21(4):349-54.
6. Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada K, Fossdal R, et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet (London, England). 2010;376(9750):1401-8.
7. Faraone SV, Biederman J. Is attention deficit hyperactivity disorder familial? Harvard review of psychiatry. 1994;1(5):271-87.
8. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biological psychiatry. 2005;57(11):1313-23.
9. Faraone SV, Mick E. Molecular genetics of attention deficit hyperactivity disorder. The Psychiatric clinics of North America. 2010;33(1):159-80.
10. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747-53.
11. Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry. 2019;24(4):562-75.
12. Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychological medicine. 2006;36(2):159-65.
13. Lara C, Fayyad J, de Graaf R, Kessler RC, Aguilar-Gaxiola S, Angermeyer M, et al. Childhood predictors of adult attention-deficit/hyperactivity disorder: results from the World Health Organization World Mental Health Survey Initiative. Biological psychiatry. 2009;65(1):46-54.
14. Rutter M, Kim-Cohen J, Maughan B. Continuities and discontinuities in psychopathology between childhood and adult life. Journal of child psychology and psychiatry, and allied disciplines. 2006;47(3-4):276-95.
15. Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Human genetics. 2009;126(1):51-90.
16. Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature genetics. 2019;51(1):63-75.
17. McClellan J, King MC. Genetic heterogeneity in human disease. Cell. 2010;141(2):210-7.
18. Anway MD, Skinner MK. Epigenetic programming of the germ line: effects of endocrine disruptors on the development of transgenerational disease. Reproductive biomedicine online. 2008;16(1):23-5.
19. Ashe A, Whitelaw E. Another role for RNA: a messenger across generations. Trends in genetics : TIG. 2007;23(1):8-10.
20. Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature. 2006;441(7092):469-74.
21. Jin P, Alisch RS, Warren ST. RNA and microRNAs in fragile X mental retardation. Nature cell biology. 2004;6(11):1048-53.
22. Camkurt MA, Karababa F, Erdal ME, Bayazıt H, Kandemir SB, Ay ME, et al. Investigation of Dysregulation of Several MicroRNAs in Peripheral Blood of Schizophrenia Patients. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology. 2016;14(3):256-60.
23. 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 biology. 2007;8(2):R27.
24. Sarachana T, Zhou R, Chen G, Manji HK, Hu VW. Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines. Genome medicine. 2010;2(4):23.
25. Lukiw WJ, Zhao Y, Cui JG. An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. The Journal of biological chemistry. 2008;283(46):31315-22.
26. Maes OC, Chertkow HM, Wang E, Schipper HM. MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders. Current genomics. 2009;10(3):154-68.
27. Wu LH, Peng M, Yu M, Zhao QL, Li C, Jin YT, et al. Circulating MicroRNA Let-7d in Attention-Deficit/Hyperactivity Disorder. Neuromolecular medicine. 2015;17(2):137-46.
28. Kovács-Nagy R, Hu J, Rónai Z, Sasvári-Székely M. SNAP-25: a novel candidate gene in psychiatric genetics. Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology. 2009;11(2):89-94.
29. Kovacs-Nagy R, Sarkozy P, Hu J, Guttman A, Sasvari-Szekely M, Ronai Z. Haplotyping of putative microRNA-binding sites in the SNAP-25 gene. Electrophoresis. 2011;32(15):2013-20.
30. Garcia-Martínez I, Sánchez-Mora C, Pagerols M, Richarte V, Corrales M, Fadeuilhe C, et al. Preliminary evidence for association of genetic variants in pri-miR-34b/c and abnormal miR-34c expression with attention deficit and hyperactivity disorder. Translational psychiatry. 2016;6(8):e879.
31. Wang LJ, Li SC, Kuo HC, Chou WJ, Lee MJ, Chou MC, et al. Gray matter volume and microRNA levels in patients with attention-deficit/hyperactivity disorder. European archives of psychiatry and clinical neuroscience. 2019.
32. Aydin SU, Kabukcu Basay B, Cetin GO, Gungor Aydin A, Tepeli E. Altered microRNA 5692b and microRNA let-7d expression levels in children and adolescents with attention deficit hyperactivity disorder. Journal of psychiatric research. 2019;115:158-64.
33. Sánchez-Mora C, Soler Artigas M, Garcia-Martínez I, Pagerols M, Rovira P, Richarte V, et al. Epigenetic signature for attention-deficit/hyperactivity disorder: identification of miR-26b-5p, miR-185-5p, and miR-191-5p as potential biomarkers in peripheral blood mononuclear cells. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2019;44(5):890-7.
34. Cao P, Wang L, Cheng Q, Sun X, Kang Q, Dai L, 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. Psychiatry research. 2019;274:189-94.
35. Zhang L, Chang S, Li Z, Zhang K, Du Y, Ott J, et al. ADHDgene: a genetic database for attention deficit hyperactivity disorder. Nucleic Acids Res. 2012;40(Database issue):D1003-9.
36. Piñero J, Bravo À, Queralt-Rosinach N, Gutiérrez-Sacristán A, Deu-Pons J, Centeno E, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 2017;45(D1):D833-d9.
37. Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Current protocols in bioinformatics. 2016;54:1.30.1-1..3.
38. Alonso-Gonzalez A, Calaza M, Rodriguez-Fontenla C, Carracedo A. Gene-based analysis of ADHD using PASCAL: a biological insight into the novel associated genes. BMC medical genomics. 2019;12(1):143.
39. Ghandikota S, Hershey GKK, Mersha TB. GENEASE: real time bioinformatics tool for multi-omics and disease ontology exploration, analysis and visualization. Bioinformatics (Oxford, England). 2018;34(18):3160-8.
40. Miller JA, Ding S-L, Sunkin SM, Smith KA, Ng L, Szafer A, et al. Transcriptional landscape of the prenatal human brain. Nature. 2014;508(7495):199-206.
41. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Research. 2015;43(7):e47-e.
42. Licursi V, Conte F, Fiscon G, Paci P. MIENTURNET: an interactive web tool for microRNA-target enrichment and network-based analysis. BMC Bioinformatics. 2019;20(1):545.
43. Huang H-Y, Lin Y-C-D, Li J, Huang K-Y, Shrestha S, Hong H-C, et al. miRTarBase 2020: updates to the experimentally validated microRNA–target interaction database. Nucleic Acids Research. 2019;48(D1):D148-D54.
44. 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 research. 2003;13(11):2498-504.
45. da Silveira WA, Renaud L, Simpson J, Glen WB, Jr., Hazard ES, Chung D, et al. miRmapper: A Tool for Interpretation of miRNA⁻mRNA Interaction Networks. Genes. 2018;9(9).
46. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics (Oxford, England). 2010;26(1):139-40.
47. Dougherty JD, Schmidt EF, Nakajima M, Heintz N. Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells. Nucleic Acids Res. 2010;38(13):4218-30.
48. Kim J, Krichevsky A, Grad Y, Hayes GD, Kosik KS, Church GM, et al. Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(1):360-5.
49. Parsons MJ, Grimm CH, Paya-Cano JL, Sugden K, Nietfeld W, Lehrach H, et al. Using hippocampal microRNA expression differences between mouse inbred strains to characterise miRNA function. Mammalian genome : official journal of the International Mammalian Genome Society. 2008;19(7-8):552-60.
50. Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper RA, Webb SJ. Autism and abnormal development of brain connectivity. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004;24(42):9228-31.
51. Duale N, Eide DM, Amberger ML, Graupner A, Brede DA, Olsen AK. Using prediction models to identify miRNA-based markers of low dose rate chronic stress. The Science of the total environment. 2020;717:137068.
52. Peter ME. Targeting of mRNAs by multiple miRNAs: the next step. Oncogene. 2010;29(15):2161-4.
53. Concepcion CP, Bonetti C, Ventura A. The microRNA-17-92 family of microRNA clusters in development and disease. Cancer journal (Sudbury, Mass). 2012;18(3):262-7.
54. Finnerty JR, Wang WX, Hébert SS, Wilfred BR, Mao G, Nelson PT. The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseases. Journal of molecular biology. 2010;402(3):491-509.
55. Proal E, Reiss PT, Klein RG, Mannuzza S, Gotimer K, Ramos-Olazagasti MA, et al. Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Archives of general psychiatry. 2011;68(11):1122-34.
56. Ellison-Wright I, Ellison-Wright Z, Bullmore E. Structural brain change in Attention Deficit Hyperactivity Disorder identified by meta-analysis. BMC psychiatry. 2008;8:51.
57. Nakao T, Radua J, Rubia K, Mataix-Cols D. Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. The American journal of psychiatry. 2011;168(11):1154-63.
58. Valera EM, Faraone SV, Murray KE, Seidman LJ. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biological psychiatry. 2007;61(12):1361-9.
59. Hoogman M, Rijpkema M, Janss L, Brunner H, Fernandez G, Buitelaar J, et al. Current self-reported symptoms of attention deficit/hyperactivity disorder are associated with total brain volume in healthy adults. PloS one. 2012;7(2):e31273.
60. Silbereis JC, Pochareddy S, Zhu Y, Li M, Sestan N. The Cellular and Molecular Landscapes of the Developing Human Central Nervous System. Neuron. 2016;89(2):248-68.
61. Nowak JS, Michlewski G. miRNAs in development and pathogenesis of the nervous system. Biochemical Society transactions. 2013;41(4):815-20.
62. Adlakha YK, Saini N. Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Molecular cancer. 2014;13:33.
63. Shao NY, Hu HY, Yan Z, Xu Y, Hu H, Menzel C, et al. Comprehensive survey of human brain microRNA by deep sequencing. BMC genomics. 2010;11:409.
64. Delaloy C, Liu L, Lee JA, Su H, Shen F, Yang GY, et al. MicroRNA-9 coordinates proliferation and migration of human embryonic stem cell-derived neural progenitors. Cell stem cell. 2010;6(4):323-35.
65. Coolen M, Katz S, Bally-Cuif L. miR-9: a versatile regulator of neurogenesis. Frontiers in cellular neuroscience. 2013;7:220.
66. Makeyev EV, Zhang J, Carrasco MA, Maniatis T. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Molecular cell. 2007;27(3):435-48.
67. Cheng LC, Pastrana E, Tavazoie M, Doetsch F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nature neuroscience. 2009;12(4):399-408.
68. Zhao C, Sun G, Li S, Shi Y. A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nature structural & molecular biology. 2009;16(4):365-71.
69. Clovis YM, Enard W, Marinaro F, Huttner WB, De Pietri Tonelli D. Convergent repression of Foxp2 3'UTR by miR-9 and miR-132 in embryonic mouse neocortex: implications for radial migration of neurons. Development (Cambridge, England). 2012;139(18):3332-42.
70. Conaco C, Otto S, Han JJ, Mandel G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(7):2422-7.
71. Tan X, Wang S, Yang B, Zhu L, Yin B, Chao T, et al. The CREB-miR-9 negative feedback minicircuitry coordinates the migration and proliferation of glioma cells. PloS one. 2012;7(11):e49570.
72. Tan SL, Ohtsuka T, González A, Kageyama R. MicroRNA9 regulates neural stem cell differentiation by controlling Hes1 expression dynamics in the developing brain. Genes to cells : devoted to molecular & cellular mechanisms. 2012;17(12):952-61.
73. Åkerblom M, Jakobsson J. MicroRNAs as Neuronal Fate Determinants. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2014;20(3):235-42.
74. Muddashetty RS, Nalavadi VC, Gross C, Yao X, Xing L, Laur O, et al. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Molecular cell. 2011;42(5):673-88.
75. Sosanya NM, Brager DH, Wolfe S, Niere F, Raab-Graham KF. Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis. Neurobiology of disease. 2015;73:96-105.
76. Kocerha J, Kauppinen S, Wahlestedt C. microRNAs in CNS disorders. Neuromolecular medicine. 2009;11(3):162-72.
77. Zhang Y, Ueno Y, Liu XS, Buller B, Wang X, Chopp M, et al. The MicroRNA-17-92 cluster enhances axonal outgrowth in embryonic cortical neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2013;33(16):6885-94.
78. Agostini M, Tucci P, Steinert JR, Shalom-Feuerstein R, Rouleau M, Aberdam D, et al. microRNA-34a regulates neurite outgrowth, spinal morphology, and function. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(52):21099-104.
79. Kandemir H, Erdal ME, Selek S, Ay Ö, Karababa IF, Kandemir SB, et al. Evaluation of several micro RNA (miRNA) levels in children and adolescents with attention deficit hyperactivity disorder. Neuroscience letters. 2014;580:158-62.
80. Jovicic A, Zaldivar Jolissaint JF, Moser R, Silva Santos Mde F, Luthi-Carter R. MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington's disease-related mechanisms. PloS one. 2013;8(1):e54222.
81. Ma J, Shang S, Wang J, Zhang T, Nie F, Song X, et al. Identification of miR-22-3p, miR-92a-3p, and miR-137 in peripheral blood as biomarker for schizophrenia. Psychiatry research. 2018;265:70-6.
82. Kang M-J, Park S-Y, Han J-S. MicroRNA-24-3p regulates neuronal differentiation by controlling hippocalcin expression. Cellular and Molecular Life Sciences. 2019;76(22):4569-80.
83. Heberle H, Meirelles GV, da Silva FR, Telles GP, Minghim R. InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams. BMC Bioinformatics. 2015;16(1):169.
2. Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. Journal of child psychology and psychiatry, and allied disciplines. 2015;56(3):345-65.
3. Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics. 2015;135(4):e994-1001.
4. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author. http://dx.doi.org/10.1176/appi.books.9780890425596. American Psychiatric Association Publishing2013.
5. Biedermann F, Fleischhacker WW. Psychotic disorders in DSM-5 and ICD-11. CNS spectrums. 2016;21(4):349-54.
6. Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada K, Fossdal R, et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet (London, England). 2010;376(9750):1401-8.
7. Faraone SV, Biederman J. Is attention deficit hyperactivity disorder familial? Harvard review of psychiatry. 1994;1(5):271-87.
8. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biological psychiatry. 2005;57(11):1313-23.
9. Faraone SV, Mick E. Molecular genetics of attention deficit hyperactivity disorder. The Psychiatric clinics of North America. 2010;33(1):159-80.
10. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747-53.
11. Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry. 2019;24(4):562-75.
12. Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychological medicine. 2006;36(2):159-65.
13. Lara C, Fayyad J, de Graaf R, Kessler RC, Aguilar-Gaxiola S, Angermeyer M, et al. Childhood predictors of adult attention-deficit/hyperactivity disorder: results from the World Health Organization World Mental Health Survey Initiative. Biological psychiatry. 2009;65(1):46-54.
14. Rutter M, Kim-Cohen J, Maughan B. Continuities and discontinuities in psychopathology between childhood and adult life. Journal of child psychology and psychiatry, and allied disciplines. 2006;47(3-4):276-95.
15. Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Human genetics. 2009;126(1):51-90.
16. Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature genetics. 2019;51(1):63-75.
17. McClellan J, King MC. Genetic heterogeneity in human disease. Cell. 2010;141(2):210-7.
18. Anway MD, Skinner MK. Epigenetic programming of the germ line: effects of endocrine disruptors on the development of transgenerational disease. Reproductive biomedicine online. 2008;16(1):23-5.
19. Ashe A, Whitelaw E. Another role for RNA: a messenger across generations. Trends in genetics : TIG. 2007;23(1):8-10.
20. Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature. 2006;441(7092):469-74.
21. Jin P, Alisch RS, Warren ST. RNA and microRNAs in fragile X mental retardation. Nature cell biology. 2004;6(11):1048-53.
22. Camkurt MA, Karababa F, Erdal ME, Bayazıt H, Kandemir SB, Ay ME, et al. Investigation of Dysregulation of Several MicroRNAs in Peripheral Blood of Schizophrenia Patients. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology. 2016;14(3):256-60.
23. 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 biology. 2007;8(2):R27.
24. Sarachana T, Zhou R, Chen G, Manji HK, Hu VW. Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines. Genome medicine. 2010;2(4):23.
25. Lukiw WJ, Zhao Y, Cui JG. An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. The Journal of biological chemistry. 2008;283(46):31315-22.
26. Maes OC, Chertkow HM, Wang E, Schipper HM. MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders. Current genomics. 2009;10(3):154-68.
27. Wu LH, Peng M, Yu M, Zhao QL, Li C, Jin YT, et al. Circulating MicroRNA Let-7d in Attention-Deficit/Hyperactivity Disorder. Neuromolecular medicine. 2015;17(2):137-46.
28. Kovács-Nagy R, Hu J, Rónai Z, Sasvári-Székely M. SNAP-25: a novel candidate gene in psychiatric genetics. Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology. 2009;11(2):89-94.
29. Kovacs-Nagy R, Sarkozy P, Hu J, Guttman A, Sasvari-Szekely M, Ronai Z. Haplotyping of putative microRNA-binding sites in the SNAP-25 gene. Electrophoresis. 2011;32(15):2013-20.
30. Garcia-Martínez I, Sánchez-Mora C, Pagerols M, Richarte V, Corrales M, Fadeuilhe C, et al. Preliminary evidence for association of genetic variants in pri-miR-34b/c and abnormal miR-34c expression with attention deficit and hyperactivity disorder. Translational psychiatry. 2016;6(8):e879.
31. Wang LJ, Li SC, Kuo HC, Chou WJ, Lee MJ, Chou MC, et al. Gray matter volume and microRNA levels in patients with attention-deficit/hyperactivity disorder. European archives of psychiatry and clinical neuroscience. 2019.
32. Aydin SU, Kabukcu Basay B, Cetin GO, Gungor Aydin A, Tepeli E. Altered microRNA 5692b and microRNA let-7d expression levels in children and adolescents with attention deficit hyperactivity disorder. Journal of psychiatric research. 2019;115:158-64.
33. Sánchez-Mora C, Soler Artigas M, Garcia-Martínez I, Pagerols M, Rovira P, Richarte V, et al. Epigenetic signature for attention-deficit/hyperactivity disorder: identification of miR-26b-5p, miR-185-5p, and miR-191-5p as potential biomarkers in peripheral blood mononuclear cells. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2019;44(5):890-7.
34. Cao P, Wang L, Cheng Q, Sun X, Kang Q, Dai L, 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. Psychiatry research. 2019;274:189-94.
35. Zhang L, Chang S, Li Z, Zhang K, Du Y, Ott J, et al. ADHDgene: a genetic database for attention deficit hyperactivity disorder. Nucleic Acids Res. 2012;40(Database issue):D1003-9.
36. Piñero J, Bravo À, Queralt-Rosinach N, Gutiérrez-Sacristán A, Deu-Pons J, Centeno E, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 2017;45(D1):D833-d9.
37. Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Current protocols in bioinformatics. 2016;54:1.30.1-1..3.
38. Alonso-Gonzalez A, Calaza M, Rodriguez-Fontenla C, Carracedo A. Gene-based analysis of ADHD using PASCAL: a biological insight into the novel associated genes. BMC medical genomics. 2019;12(1):143.
39. Ghandikota S, Hershey GKK, Mersha TB. GENEASE: real time bioinformatics tool for multi-omics and disease ontology exploration, analysis and visualization. Bioinformatics (Oxford, England). 2018;34(18):3160-8.
40. Miller JA, Ding S-L, Sunkin SM, Smith KA, Ng L, Szafer A, et al. Transcriptional landscape of the prenatal human brain. Nature. 2014;508(7495):199-206.
41. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Research. 2015;43(7):e47-e.
42. Licursi V, Conte F, Fiscon G, Paci P. MIENTURNET: an interactive web tool for microRNA-target enrichment and network-based analysis. BMC Bioinformatics. 2019;20(1):545.
43. Huang H-Y, Lin Y-C-D, Li J, Huang K-Y, Shrestha S, Hong H-C, et al. miRTarBase 2020: updates to the experimentally validated microRNA–target interaction database. Nucleic Acids Research. 2019;48(D1):D148-D54.
44. 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 research. 2003;13(11):2498-504.
45. da Silveira WA, Renaud L, Simpson J, Glen WB, Jr., Hazard ES, Chung D, et al. miRmapper: A Tool for Interpretation of miRNA⁻mRNA Interaction Networks. Genes. 2018;9(9).
46. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics (Oxford, England). 2010;26(1):139-40.
47. Dougherty JD, Schmidt EF, Nakajima M, Heintz N. Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells. Nucleic Acids Res. 2010;38(13):4218-30.
48. Kim J, Krichevsky A, Grad Y, Hayes GD, Kosik KS, Church GM, et al. Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(1):360-5.
49. Parsons MJ, Grimm CH, Paya-Cano JL, Sugden K, Nietfeld W, Lehrach H, et al. Using hippocampal microRNA expression differences between mouse inbred strains to characterise miRNA function. Mammalian genome : official journal of the International Mammalian Genome Society. 2008;19(7-8):552-60.
50. Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper RA, Webb SJ. Autism and abnormal development of brain connectivity. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004;24(42):9228-31.
51. Duale N, Eide DM, Amberger ML, Graupner A, Brede DA, Olsen AK. Using prediction models to identify miRNA-based markers of low dose rate chronic stress. The Science of the total environment. 2020;717:137068.
52. Peter ME. Targeting of mRNAs by multiple miRNAs: the next step. Oncogene. 2010;29(15):2161-4.
53. Concepcion CP, Bonetti C, Ventura A. The microRNA-17-92 family of microRNA clusters in development and disease. Cancer journal (Sudbury, Mass). 2012;18(3):262-7.
54. Finnerty JR, Wang WX, Hébert SS, Wilfred BR, Mao G, Nelson PT. The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseases. Journal of molecular biology. 2010;402(3):491-509.
55. Proal E, Reiss PT, Klein RG, Mannuzza S, Gotimer K, Ramos-Olazagasti MA, et al. Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Archives of general psychiatry. 2011;68(11):1122-34.
56. Ellison-Wright I, Ellison-Wright Z, Bullmore E. Structural brain change in Attention Deficit Hyperactivity Disorder identified by meta-analysis. BMC psychiatry. 2008;8:51.
57. Nakao T, Radua J, Rubia K, Mataix-Cols D. Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. The American journal of psychiatry. 2011;168(11):1154-63.
58. Valera EM, Faraone SV, Murray KE, Seidman LJ. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biological psychiatry. 2007;61(12):1361-9.
59. Hoogman M, Rijpkema M, Janss L, Brunner H, Fernandez G, Buitelaar J, et al. Current self-reported symptoms of attention deficit/hyperactivity disorder are associated with total brain volume in healthy adults. PloS one. 2012;7(2):e31273.
60. Silbereis JC, Pochareddy S, Zhu Y, Li M, Sestan N. The Cellular and Molecular Landscapes of the Developing Human Central Nervous System. Neuron. 2016;89(2):248-68.
61. Nowak JS, Michlewski G. miRNAs in development and pathogenesis of the nervous system. Biochemical Society transactions. 2013;41(4):815-20.
62. Adlakha YK, Saini N. Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Molecular cancer. 2014;13:33.
63. Shao NY, Hu HY, Yan Z, Xu Y, Hu H, Menzel C, et al. Comprehensive survey of human brain microRNA by deep sequencing. BMC genomics. 2010;11:409.
64. Delaloy C, Liu L, Lee JA, Su H, Shen F, Yang GY, et al. MicroRNA-9 coordinates proliferation and migration of human embryonic stem cell-derived neural progenitors. Cell stem cell. 2010;6(4):323-35.
65. Coolen M, Katz S, Bally-Cuif L. miR-9: a versatile regulator of neurogenesis. Frontiers in cellular neuroscience. 2013;7:220.
66. Makeyev EV, Zhang J, Carrasco MA, Maniatis T. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Molecular cell. 2007;27(3):435-48.
67. Cheng LC, Pastrana E, Tavazoie M, Doetsch F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nature neuroscience. 2009;12(4):399-408.
68. Zhao C, Sun G, Li S, Shi Y. A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nature structural & molecular biology. 2009;16(4):365-71.
69. Clovis YM, Enard W, Marinaro F, Huttner WB, De Pietri Tonelli D. Convergent repression of Foxp2 3'UTR by miR-9 and miR-132 in embryonic mouse neocortex: implications for radial migration of neurons. Development (Cambridge, England). 2012;139(18):3332-42.
70. Conaco C, Otto S, Han JJ, Mandel G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(7):2422-7.
71. Tan X, Wang S, Yang B, Zhu L, Yin B, Chao T, et al. The CREB-miR-9 negative feedback minicircuitry coordinates the migration and proliferation of glioma cells. PloS one. 2012;7(11):e49570.
72. Tan SL, Ohtsuka T, González A, Kageyama R. MicroRNA9 regulates neural stem cell differentiation by controlling Hes1 expression dynamics in the developing brain. Genes to cells : devoted to molecular & cellular mechanisms. 2012;17(12):952-61.
73. Åkerblom M, Jakobsson J. MicroRNAs as Neuronal Fate Determinants. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2014;20(3):235-42.
74. Muddashetty RS, Nalavadi VC, Gross C, Yao X, Xing L, Laur O, et al. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Molecular cell. 2011;42(5):673-88.
75. Sosanya NM, Brager DH, Wolfe S, Niere F, Raab-Graham KF. Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis. Neurobiology of disease. 2015;73:96-105.
76. Kocerha J, Kauppinen S, Wahlestedt C. microRNAs in CNS disorders. Neuromolecular medicine. 2009;11(3):162-72.
77. Zhang Y, Ueno Y, Liu XS, Buller B, Wang X, Chopp M, et al. The MicroRNA-17-92 cluster enhances axonal outgrowth in embryonic cortical neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2013;33(16):6885-94.
78. Agostini M, Tucci P, Steinert JR, Shalom-Feuerstein R, Rouleau M, Aberdam D, et al. microRNA-34a regulates neurite outgrowth, spinal morphology, and function. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(52):21099-104.
79. Kandemir H, Erdal ME, Selek S, Ay Ö, Karababa IF, Kandemir SB, et al. Evaluation of several micro RNA (miRNA) levels in children and adolescents with attention deficit hyperactivity disorder. Neuroscience letters. 2014;580:158-62.
80. Jovicic A, Zaldivar Jolissaint JF, Moser R, Silva Santos Mde F, Luthi-Carter R. MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington's disease-related mechanisms. PloS one. 2013;8(1):e54222.
81. Ma J, Shang S, Wang J, Zhang T, Nie F, Song X, et al. Identification of miR-22-3p, miR-92a-3p, and miR-137 in peripheral blood as biomarker for schizophrenia. Psychiatry research. 2018;265:70-6.
82. Kang M-J, Park S-Y, Han J-S. MicroRNA-24-3p regulates neuronal differentiation by controlling hippocalcin expression. Cellular and Molecular Life Sciences. 2019;76(22):4569-80.
83. Heberle H, Meirelles GV, da Silva FR, Telles GP, Minghim R. InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams. BMC Bioinformatics. 2015;16(1):169.