Ho potoloha Maemo a Maikutlo a MicroRNA a Amanang le Inthanete Mathateng a ho Bapala (2018)

. 2018; 9: 81.

E hatisitsoe Inthaneteng 2018 Mar 12. doi:  10.3389 / fpsyt.2018.00081

PMCID: PMC5858605

PMID: 29593587

inahaneloang

Background

Tšebeliso e mpe ea lipapali tsa marang-rang le marang-rang ke bokuli bo ka bakang mafu a kelello a bitsoang ho bapala lipapali tsa inthanete (IGD). Lifilosofi tse fetotsoeng tsa microRNA (miRNA) li tlalehiloe ka har'a mali le bokong ba bakuli ba nang le mathata a itseng a kelello mme ba khothaletsoa e le biomarkers. Leha ho le joalo, ha ho e-so be le litlaleho mabapi le profiles tsa miRNA ea mali ho IGD.

mekhoa

Ho fumana li-miRNA tse amanang le IGD, re ile ra sekaseka lintlha tsa tlhahiso ea li-miRNA tsa sampole tsa 51 (25 IGD le 26 control) re sebelisa TaqMan Low Density miRNA Array. Bakeng sa netefatso, re sebelisitse PCR ea bongata bo lekanyelitsoeng ka lipampiri tse ikemetseng tsa 36 (20 IGD le 16 control).

Results

Ka ho sibolla le netefatso e ikemetseng, re bonts'itse li-miRNA tse tharo (hsa-miR-200c-3p, hsa-miR-26b-5p, hsa-miR-652-3p) tse neng li theotsoe haholo sehlopheng sa IGD. Batho ka bomong ba nang le liphetoho tsohle tsa miRNA tse tharo ba ne ba na le kotsi e kholo ea IGD ho feta e se nang liphetoho [karo-karolelano ea (OR) 22, 95% CI 2.29-211.11], 'me li-ORs li ile tsa eketseha ka tekanyetso ka palo ka li-miRNA tse fetotsoeng. Mefuta e boletsoeng esale pele ea mefuta e meraro ea li-MRNA e ne e amana le litsela tsa neural. Re ile ra hlahloba polelo ea protheine ea mefuta e meraro ea sepheo se theohileng ka blot mme ra tiisa hore polelo ea GABRB2 le DPYSL2 e ne e phahame haholo sehlopheng sa IGD.

fihlela qeto e

Re hlokometse hore mantsoe a hsa-miR-200c-3p, hsa-miR-26b-5p, le hsa-miR-652-3p li ile tsa hatelloa ka tlase ho bakuli ba IGD. Liphetho tsa rona li tla thusa ho utloisisa pathophysiology ea IGD.

Keywords: Bothata ba lipapali tsa inthanete, MicroRNA, biomarker, bokhoba ba ho lemalla, blot bophirima

Selelekela

Tšebeliso e mpe ea lipapali tsa marang-rang le marang-rang ha se taba feela sechabeng linaheng tse nang le ts'ebetso e kholo ea phihlello ea marang-rang, empa bothata bo ka 'nang ba baka kelello bo reretsoeng ho bapala papali ea Inthanete (IGD) (-). Ho ea ka litlaleho tsa lefu la seoa, lenane la ho ata ha IGD ho bacha le fapana ho pholletsa le linaha, ho tloha ho 0.8 ho isa 26.7% (). Haholo-holo liphuputso li bonts'a litekanyetso tsa kholo ea batho ba bangata kaholimo ho 10% ho bacha linaheng tse ngata tsa Asia tse kang Korea Boroa, China, Taiwan, Hong Kong le Singapore (). IGD e amahanngoa le ho senyeha kelellong, likamano tsa kelello le sechaba, le bophelo ba letsatsi le letsatsi; mohlala, ho fokotseha hoa maemo a thuto kapa a mosebetsi.-). IGD hajoale e kenyellelitsoe Karolong ea boraro (Maemo a Thutong e Eketsehileng) ea tlhahlobo ea bohlano ea Diagnostic and Statistical Manual of Mental Dis shida (DSM-V) (). Leha ho le joalo, ho sa tsotelloe bohlokoa ba eona ba kliniki le sechabeng, ha ho tsejoe ka mochini oa liphatsa tsa lefutso o ka morao ho IGD.

Boithuto ba morao-rao bo boholo bo bontšitse mofuta oa lefutso ho IGD (, ). Vink et al. fuputsa liphapang tsa motho ka mong ka ts'ebeliso e qobelloang ea tšebeliso ea inthanete le mafahla a lilemong tsa bocha tsa 5,247 le li-dizygotic ho Netherlands Twin Register mme a tlaleha hore liphapang tsa 48% li hlalositsoe ke mabaka a liphatsa tsa lefutso (). Li et al. o hlokometse lipara tsa 825 tsa mafahla a bocha ba China mme a tlaleha hore lintlha tsa lefutso li hlalositse 58-66% ea liphapang (). Ka hona, li-polymorphism tsa mefuta ea karolo tse amehang ho ts'ebetso ea methapo, kutloisiso le tlhokomelo e joalo ka mofuta oa dopamine receptor D2 gene (DRD2), catecholamine-O-methyltransferase gene (COMT), serotonin transporter gene (5HTTLPR), le mofuta oa cholinergic receptor nicotinic alpha 4 gene (CHRNA4) ho tlalehiloe hore li amana haholo le bokhoba ba marang-rang (-). Haufinyane tjena, Kim et al. e hlahlobe mefuta e mengata ea mefuta e fetang ea 100 e amanang le tlhahiso, ketso, le metabolism ea li-neurotransmitters ka tlhahlobo ea tatellano ea meloko e latelang mme e tlaleha hore rs2229910 ea NTRK3 gene e amahanngoa le IGD ().

Ntle le lintlha tsa liphatsa tsa lefutso, ho boetse ho tsebahala hore li-phenotypes tsa neurobehaeveal li laoloa ka tsela epigenetically ke li-RNA tse sa kopaneng ho kenyelletsa li-MicroRNA (miRNAs) (, ). miRNA ke limolek'hule tse fokolang tsa RNA tse se nang li-single tsa strNA (hoo e ka bang 20-23 li-nucleotide ka bolelele), tse sa laoleng polelo e buang ka liphatsa tsa lefutso tsa protheine ka li-MRNA tse mpe mme li bapala karolo ea bohlokoa ts'ebetsong ea pathophysiological ea mafu a fapaneng.). Mehloli ea bopaki e bonts'itse hore li-miRNA li ngata ka har'a tsamaiso ea methapo ea motho (CNS) le ho nka khato e hlakileng ea maemo a polelo a mofuta oa tsona, a amehang ntlafatsong le mofuteng oa tsamaiso ea CNS (). Ka sebele, liphuputso tsa morao-rao li senotse hore li-profiles tsa miRNA li fetotsoe liseleng tsa boko ba bakuli ba nang le mafu a kelello, ba fana ka maikutlo a hore lintlha tsa bona tsa polelo e ka ba li-biomarkers bakeng sa mafu a kelello (, , ). Mohlala, ka tlhahlobo ea postmortem, Lopez et al. e tlaleha hore polelo ea miR-1202, e laolang polelo ea mofuta oa metabotropic glutamate receptor-4 mme e bolela esale pele karabelo ho antidepressant, e ne e theotsoe ka pele ho li-tishu tsa cortex tsa pele ho khatello ea maikutlo ea bakuli ba khatello ea maikutlo (). Mabapi le tlhaiso ea biomarker, mokhoa ona o na le moeli o hlakileng hobane ho etsa li-biopsy tsa CNS bakeng sa ho hlahlobeloa ha ho khonehe. Kaha li-miRNA li ka bonoa maling (plasma kapa serum), li-miRNA tse potileng li na le molemo o hlakileng e le li-biomarkers tse sa hlaseleng boteng ba neuropsychiatric. Leha ho le joalo, ho fihlela joale, ha ho na lithuto tse mabapi le ho potoloha lifaele tsa miRNA ho IGD. Kutloisiso e ntlafalitsoeng ea lifaele tsa polelo ea miRNA e ka thusa ho hlakisa mochini oa nts'etsopele ea IGD le ho tsamaisa phetolelo ea bongaka.

Thutong ena, re ikemiselitse ho supa matšoao a amanang le li-IGR ka ho shebella ka ho fapana lipono tsa li-plasma miRNA pakeng tsa IGD le lihlopha tsa taolo le ho lekola litlamorao tsa tsona tsa tlhaho.

Lisebelisoa le mekhoa

Lihlooho Tse Ithutoang

Re fuputse bacha ba 3,166 ba lilemo (12-18 lilemo tse) re sebelisa lintlha tsa DSM-V IGD. Har'a bona, banna ba 251 (ba batona ba 168 le basali ba 83) ba fumanoe e le IGD ho latela mekhoa ea DSM-V (). Kakaretso ea batho ka bomong ba 91 (49 IGDs le 42 control) ba fane ka tumello e nang le tsebo bakeng sa thuto ena. Har'a bona, batho ba bane ba ile ba qheleloa ka thoko ho latela maemo a khethollo. Qetellong, batho ba 87 (lithuto tsa 45 IGD le batho ba nang le taolo e phetseng hantle ea 42) ba ngoliselitsoe thuto ena. Har'a bona, barupeluoa ba 51 (bakuli ba 25 IGD le li-taolo tsa 26) ba ile ba hapuoa ha ho sibolloa ho neng ho thehiloe ho tloha 2014 ho 2016. Barupeluoa ba bang ba 36 (bakuli ba 20 IGD le taolo ea 16) ba ile ba hapuoa e le netefatso e ikemetseng e behiloeng ho 2016. Barupeluoa bohle e ne e le batho ba Korea, ba ngoliselitsoeng ho tsoa sepetleleng sa Seoul St. Mary's (Seoul, Korea Boroa) le Seoul National University Boramae Hospital (Seoul, Korea Boroa). Barupeluoa bohle ba entse tlhahlobo e hlophisitsoeng ke ngaka ea mafu a kelello e thehiloeng ho Lenaneo la Kiddie la Korea bakeng sa Mathata a Kopaneng le Schizophrenia (K-SADS-PL) (). Barupeluoa bohle ba phethile karoloana ea "Design Design le Vocabulary" ea Sekolo sa bana ba Korea-Wechsler Intelligence Scale, 4th (K-WISC-IV) (). Ho hloka matla ho ile ha hlahlojoa ke Barratt Impulsiveness Scale (BIS) (). Sekala sa Behaeveal Inhibition System (BInS) le Behaeveal activation System (BAS) se ile sa lekanyetsoa ho lekola boholo ba botho (). Litekanyetso tsa ho kenyelletsa li kenyelletsa mathata a maholo a nakong e fetileng kapa a hona joale a bongaka (mohlala, lefu la tsoekere, lefu la mokokotlo (mohlala, ho ts'oaroa ke hlooho, likotsi tsa hlooho), mafu a kelello (mohlala, khatello e kholo ea maikutlo, mathata a ho tšoenyeha), ho khutlela morao kelellong, kapa tlhekefetso efe kapa efe ea lithethefatsi (mohlala, , koae, cannabis, joala). Litšobotsi tse akaretsang tsa lithuto tse ithutoang li akaretsoa ho Tafole Lethathamo1.1. Boithuto bona bo amohetsoe ke Institutional Review Board ea Katolike University Medical Medical of Korea (MC16SISI0120). Barupeluoa bohle le batsoali ba bona ba fane ka tumello e ngotsoeng.

Lethathamo 1

Litšoaneleho tse akaretsang tsa lithuto tse ithutoang.

 sibolloaTlhalosoKopantswe
 
 ControlIGDP-senoloControlIGDP-senoloControlIGDP-senolo
N2625 1620 4245 
Lilemo (lilemo)
Medi (min-max)13 (12 - 17)13 (12 - 15)0.75915 (13 - 18)14.5 (12 - 18)0.62814 (12 - 18)14 (12 - 18)0.509
Lihora tsa beke le beke tsa lipapali tsa marang-rang (h)
Medi (min-max)5.25 (2 - 17)18 (6 - 46)1.27E − 6a5.5 (2 - 23)8 (1 - 112)0.3745.5 (2 - 23)14 (1 - 112)1.63E − 5a
Chelete ea khoeli le khoeli ea ntlo (KRW milione)
Medi (min-max)5 (1 - 9)3 (1 - 9)0.5884 (4 - 4)2 (2 - 2)1.0005 (1 - 9)3 (1 - 9)0.460
Thuto (lilemo)
Medi (min-max)8 (7 - 9)8 (7 - 9)0.58412 (12 - 12)6 (6 - 13)0.3058 (7 - 12)8 (6 - 13)0.269
K-WISC: moralo oa li-block
Medi (min-max)10.5 (4 - 17)10 (4 - 16)0.54410 (3 - 16)12.5 (4 - 15)0.12510 (3 - 17)11 (4 - 16)0.598
K-WISC: pokello ea mantsoe
Medi (min-max)9 (5 - 17)7 (5 - 13)0.1749.5 (8 - 15)11.5 (5 - 15)0.5959 (5 - 17)9 (5 - 15)0.527
KS
Medi (min-max)24 (17 - 36)37 (22 - 51)3.81E − 6a29 (17 - 34)59 (22 - 108)1.2E − 5a25 (17 - 36)40 (22 - 108)2.05E − 10a
BIS
Medi (min-max)63 (35 - 75)67.5 (45 - 81)0.08061 (45 - 79)63 (32 - 82)0.83562 (35 - 79)65 (32 - 82)0.240
Bas
Medi (min-max)31 (15 - 40)31 (13 - 51)0.55836.5 (22 - 48)34 (27 - 52)1.00032 (15 - 48)34 (13 - 52)0.637
MABITLE
Medi (min-max)18 (10 - 26)17.5 (13 - 27)0.64218.5 (12 - 25)20 (13 - 21)0.13818 (10 - 26)19 (13 - 27)0.302
 

IGD, bakuli ba nang le bothata ba lipapali tsa marang-rang; KS, Sekala sa Phokotso ea Inthanete ea Korea; BIS, Barratt Impulsivity Scale; BAS, Sistimi ea Ts'ebetso ea Behahlangual; BInS, Sisteme ea Behaeveal Inhibition; KRW, Won ea Korea.

aP <0.05 (Teko ea Mann-Whitney – Wilcoxon).

TaqMan Low Density miRNA Array (TLDA) Liteko

Mali a potoloha a ne a bokelloa ho tsoa ho setho se seng le se seng 'me a fetisetsoa laboratoring e ka har'a 4 h ho fokotsa losis ea mali. Mohlala o ne o le centrifuged ho 3,000 rpm bakeng sa 10 min ka mocheso oa kamore. Joale, supernatant (setsi sa plasma) se ile sa bokelloa ntle le ho silafatsa lisele tsa mali. LiRNA tsa ho potoloha li ile tsa ntšoa ka ho sebelisoa TaqMan miRNA ABC purization Kit (Human Panel A; Thermo Fisher Science science, Waltham, MA, USA) ho latela taelo ea moetsi. Ka bokhutšoanyane, 50 µL ea sampole ea plasma le 100 µL ea buCer ea ABC e ne e tsoakiloe. Kamora ho nyalisoa ka lieta tsa mangole tsa anti-miRNA tse tobisitsoeng, li-miRNA tse potileng li ile tsa luloa ho tloha lihloeng ka 100 µL ea buutioner elution. Karolong ea ho sibolla, 381 miRNAs e ile ea hlahlojoa ho tsoa mehlala ea 51 ea li-plasma (25 IGDs le 26 control) e sebelisa TaqMan miRNA ABC purifying Kit (Human Panel A; Thermo Fisher Science science, Waltham, MA, USA) ho latela litaelo tsa moetsi. Megaplex reverse transcript le sephetho sa pele ho ntlafatsoa li entsoe ho eketsa bongata ba cDNA bakeng sa tlhahlobo ea polelo ea miRNA ba sebelisa MegaplexPreAmp Primers Human Pool A le TaqManPreAmp Master Mix (Saense ea Moetso oa Thermo Fisher). Iphanele ea TLDA A v2.0 (Thermo Fisher Science science) e ne e tsamaisoa ho ViiA7 sistimi ea nnete ea PCR (Thermo Fisher Science science) ho lekola polelo ea li-miRNA. Lintlha tsa Raw li ile tsa sebetsoa ho sebelisoa ExpressionSuite Software v1.0.4 (Thermo Fisher Science science) ho tseba boleng ba Ct bakeng sa miRNA ka 'ngoe.

Tlhahlobo ea data bakeng sa TLDA

Re ile ra qala ka ho metha mekhahlelo (Ct boleng) ea miRNA ka ngoe. li-miRNA tse nang le boleng ba Ct> 35 li ne li nkuoa li sa bonahale ebile li sa kenyelelloa tlhahlobisong e ileng ea latela. Litekanyetso tsohle tsa Ct li ile tsa hlophisoa ka mokhoa o tloaelehileng ho boleng ba Ct ba miR-374b (boleng ba ,Ct), e leng e 'ngoe ea li-miRNA tse hlahisitsoeng hantle ka ho fetesisa tse tsamaeang ka lero la mali la motho (). Palo ea phetoho ea log2 fold (change) ea ΔΔCt) e baliloe ho sebelisoa boleng ba sampole ea taolo joaloka calibrator ka har'a sephutheloana sa HTqPCR ho Bioconductor (). Quantification e lekanyelitsoeng (RQ) ea sepheo se seng le se seng sa miRNA se ne se hlalosoa e le 2−ΔΔCt. Bakeng sa tlhahlobo ea kelello ea phapang ea polelo lipakeng tsa lihlopha tse peli, re sebelisitse tlhahlobo e fapaneng ea tlhahlobo (SVA) ho hapa li-heterogeneities joalo ka litlamorao tsa sehlopha ho liteko tse sebelisoang sva sephutheloana ka Bioconductor (). miRNAs a P-boleng <0.05 e ne e nkuoa e fapane haholo pakeng tsa lihlopha tse peli.

Ts'ebetso ea ntlafatso ea Gene

Bakeng sa tlhahlobo ea ntlafatso ea gene, re sebelisitse ToppFun ho ToppGene Suite () ho kenya tsebo e ntlafalitsoeng haholo Gene Ontology (GO) () mantsoe, tsela, le maloetse a maloetse. Ha e le monahano oa mokhoa ona, re sebelisitse 1,230 e boletseng mofuta oa sepheo sa li-miRNA. Tlhatlhobo ea tsela e sebelisitsoe ho fumana litsela tsa bohlokoa tsa mofuta oa sepheo se boletsoeng esale pele ho latela KEGG, BioCarta, Reactome, GeneMAPP, le MSigDBin tseleng ea ToppGene. Bohlokoa ba mantsoe a ntlafatsang a sebetsang bo ile ba khethoa ho ipapisitsoe le bonferroni-e ntlafalitsoeng P-senolo.

Phatlalatso ea Volitative Reverse PCR (qRT-PCR) netefatso le phetisetso

Ho netefatsa li-XRUMX miRNA tse neng li hlahisitsoe ka mokhoa o fapaneng sethaleng sa ho sibolla, qRT-PCR e entsoe ho sebelisoa TaqMan MicroRNA Assay (miR-10b-15p, #5; miR-000390b-26p, #5; miR-000407b # 29; miR-3b-000413p, #125; miR-5c-000449p, #200; miR-3-002300p, #337; miR-5-002156p, #411; miR-5-miNNXX -001610p, #423; le miR-5-002340p, #483) le sistimi ea ViiA5 (Life Technologies) ho latela protocol ea moetsi. Li-nanogram tse leshome tsa RNA e felletseng li ile tsa fetoloa hore e be li-cDNA tsa pele-strand tse nang le li-primers tse ikhethang tsa miRNA li sebelisa KitqMan MicroRNA Reverse Transcript Kit (#002338, Life Technologies), e lateloe ke PCR ea nako ea nnete e nang le TaqMan Probes. RQ ea miRNA e 'ngoe le e' ngoe e ne e hlalosoa e le 652−ΔCt, moo ΔCt e leng phapang lipakeng tsa potoloho ea sampole e botsoang, e tloaetsoeng khahlano le endRegia miRNA (miR-374b-5p, #001319). Liphetoho tsohle tsa PCR li entsoe ka makhetlo a mararo, mme boleng ba bona ba Ct bo ile ba hlakoloa. Re balile lenane la liphetoho tsa fold2 fold-change (ΔΔCt) ea miRNA ka 'ngoe ka mokhoa o ts'oanang le tlhahlobisong e thehiloeng mananeng. Teko e senang Parametric Mann-Whitney-Wilcoxon e ile ea etsoa ho leka liphapang tsa maemo a polelo ea li-miRNA ka lihlopha tse peli tse nang le monyako P-value ea 0.05.

Tlhahlobo ea Blot ea Bophirimela

Mohlala o mong le o mong oa serum o qaliloe pele ke liprotheine tse phahameng tsa 14 tse phahameng (albin, immunoglobulin G, immunoglobulin A, serotransferrin, haptoglobin, alpha-1 macroglobulin, alpha-2 acid, alpha-1ote acidly. , apolipoprotein A-II, C3, le transthyretin) e sebelisa mookotaba oa MARS-14 (4.6 × 50 mm, Agilent Technology, Santa Clara, CA, USA) pele ho tlhahlobo ea blot bophirima. Sekhechana se sa thijoeng se fumanoeng ho tsoa khorong ea MARS-14 se ile sa kenella ka matla se sebelisa filthara ea Amicon Ultracel-3 centrifugal (3 kDa cutoff), 'me joale khakanyo ea protheine e ne e ikemiselitse ho sebelisa mokhoa oa bicinchoninic acid. Litefiso tse tšoanang (ho tloha 10 ho 30 µg) ea taolo le li-sampuli tsa serum tsa IGD li arotsoe ho 4-20% Mini-PROTEAN TGX precast gel (Bio-Rad, CA, USA) mme e fetiselitsoe ho polyvinylidene difluoride membrane. Ka mor'a moo, membrane e ne e koetsoe ho TBS-T (190 mM NaCl, 25 mM Tris – HCl, pH 7.5, le 0.05% Tween 20) ka 5% lebese le sa omang le mafura ka mocheso oa kamore bakeng sa 30 min. Li-membranes li ne li kentsoe li-antibodies tsa mantlha khahlanong le DPYSL2 (1: 500, Novus Biologicals, Littleton, CO, USA), GABRB2 (1: 1000, Abcam, Cambridge, MA, USA), le CNR1 (1: 100: 4: 1: 500: 15: 1: 500: 5: 4: 1: 1,000: 1: 1,000 , Inc., Santa Cruz, CA, USA), DUSP1 (1: XNUMX, MybioSource, San Diego, CA, USA), le PIXNUMX (XNUMX: XNUMX, MybioSource, San Diego, CA, USA) ho TBS-T e nang le XNUMX % lebese le sa omang le se nang mafura ho XNUMX ° C bosiu bo le bong, 'me ka li-antibodies tse ling tsa bobeli e ka ba anti-mouse (XNUMX: XNUMX, Santa Cruz Biotechnology) kapa anti-rabi (XNUMX: XNUMX, Cell Signaling, Beverly, MA, USA ) e kopantsoeng le horseradish peroxidase mochesong oa kamore bakeng sa XNUMX h. Ho fumanoa ka lets'oao ho entsoe ho sebelisoa chemiluminescence le ECL reagent (GE healthcare, Piscataway, NJ, USA). Re hlalositse sephetho sa bophirima ka ho sebelisa software ea tlhahlobo ea TotalLab XNUMXD (Non-linear Dynamics, Newcastle upon Tyne, UK). Ebe, boleng ba densitometry ratio bo ile ba baloa ka ho arola boleng ba densitometry ba sampole ka 'ngoe joalokaha ho hlalositsoe kae kapa kae (). E le taolo bakeng sa maemo a tloaelehileng, sampole ea serum e kentsoe ho 46 IGD le li-sampuli tsa taolo e ne e sebelisoa bakeng sa teko e ngoe le e ngoe. Bohlokoa ba lipalopalo bo ile ba khethoa ba sebelisa tlhahlobo ea Mann-Whitney-Wilcoxon eo e seng parameti P-value ea 0.05.

Results

Litšobotsi tsa likarolo tsa thuto

Litaba tsa demokrasi le tsa bongaka tsa lithuto tse ithutoang li bontšitsoe ka har'a Tafole Lethathamo1.1. Ha re bapisa li-IGD le lihlopha tsa taolo ho ea ka Korea Internet Addiction Proneness Scale (K-Scale) joalo ka ha ho hlalositsoe libakeng tse ling (, ), sehlopha sa IGD se bontšitse boleng bo phahameng haholo ba K-Scale ho feta sehlopha se laolang (37 vs. 24, P = 3.81 × 10-6) (Lethathamo (Tafole1) .1). Nako ea beke ea Median e sebelisitsoeng ho papali ea marang-rang sehlopheng sa IGD e ne e le telele haholo ho feta ea li-laola (18 vs. 5.25 h, P = 1.27 × 10-6). Le ha ho ne ho sena phapang ea bohlokoa lipakeng tsa lihlopha tse peli ka lilemo, chelete ea ntlo ea khoeli le khoeli, nako ea thuto, moralo oa li-block, le sephetho se bohlale sa K-WISC, BIS, BInS le BAS.

LiRNA li hlalositsoe ka mokhoa o fapaneng lipakeng tsa IGD le Controls

Ho fumana li-miRNA tse amanang le IGD, re nkile mokhoa oa ho nka likhato tse peli (ho sibolla le ho netefatsa boikemelo). Moralo oa boithuto le leano le akaretsang li bonts'itsoe ho setšoantšo sa S1 ho Litaba tsa tlatsetso. Boemong ba ho sibolla, re ile ra sekaseka li-profiles tsa miRNA tsa li-sampuli tsa 51 (25 IGDs le 26 control) re sebelisa lihlahisoa tsa miRNA tse nang le li-384 miRNA. Maemo a hlalosang a li-10 miRNA li fumanoe li fapane haholo lipakeng tsa IGD le lihlopha tsa taolo (Tafole (Tafole2) .2). Maemo a amanang le polelo a amanang le liRNUMX miRNA tsena a bontšoa ka Setšoantšo Figure1.1. Har'a tsona, tse peli (hsa-miR-423-5p le hsa-miR-483-5p) li ile tsa ngolisoa holimo 'me tse robeli (hsa-miR-15b-5p, hsa-miR-26b-5p, hsa-miR-29b-XN hsa-miR-3b-125p, hsa-miR-5c-200p, hsa-miR-3c-337p, hsa-miR-5-411p, le sehlopha sa hsa-miR-5-652p li ne li theotsoe ka sehlopha sa IGD.

Lethathamo 2

Lits'oants'o tse fapaneng li hlalositsoe ka mokhoa o fapaneng oa li-MicroRNA (miRNAs) le liphetoho tsa mokhoeng.

miRNAsibolloaTlhalosoKopantswe
 
 P-senoloFold changeP-senoloFold changeP-senoloFold change
hsa-miR-15b-5p0.0330.8290.6941.1190.3810.947
hsa-miR-26b-5pa0.0080.8710.0490.8410.0130.857
hsa-miR-29b-3p0.0050.4000.5601.1870.0890.647
hsa-miR-125b-5p0.0210.5820.2900.9500.0690.723
hsa-miR-200c-3pa0.0110.3360.0030.5422.93 × 10-50.415
hsa-miR-337c-5p0.0090.3850.5820.8720.0200.553
hsa-miR-411-5p0.0040.3220.3361.2820.1580.595
hsa-miR-423-5p0.0261.3870.1890.9550.5181.175
hsa-miR-483-5p0.0181.8610.7651.4130.2111.647
hsa-miR-652-3pa0.0190.7150.0490.8770.0110.782
 

amiRNAs e fetotsoe haholo ho fumanoeng le ho netefalitsoeng li beha ka mokhoa o ts'oanang.

 

Faele e kantle e nang le setšoantšo, papiso, joalo-joalo Lebitso la ntho ke fpsyt-09-00081-g001.jpg

Maemo a polelo a amanang le 10 a hlalosoang ka mokhoa o fapaneng ka li-miRNA. Quantification e amanang (RQ) e ne e tloaelehile ho miR-374b-5p.

QRT-PCR netefatso ea li-miRNA tsa Mokhethoa

Ho netefatsa li-miRNA tsa mokhethoa oa 10, re ile ra etsa qRT-PCR ka sete e ikemetseng ea netefatso (taolo ea 20 IGDs le 16) (Tafole ea S1 ho Litšehetso tse Tlatsetsang). Tse tharo tsa miRNA tsena (hsa-miR-200c-3p, hsa-miR-26b-5p, le hsa-miR-652-3p) li ile tsa theoloa haholo sehlopheng sa IGD sa netefatso e behiloeng (Tafoleng (Tafole2) .2). MRNA tse ling tse tharo (hsa-miR-337c-5p, hsa-miR-125b, le hsa-miR-423-5p) le tsona li ile tsa theoloa ka sehlopa sehlopheng sa IGD empa eseng haholo. Ho boloka li-miRNAs tse nne (hsa-miR-15b-5p, hsa-miR-29b-3p, hsa-miR-411-5p, le hsa-miR-423-5p) li hlalositsoe ka mokhoa o hlakileng ho netefatso e behiloeng. Ha re kopanya lisebelisoa tsa ho sibolla le ho netefatsa (kakaretso ea lithuto tsa 45 IGD le taolo ea 42), li-miRNA tse tharo tse netefalitsoeng li ne li le bohlokoa ka mokhoa o tšoanang (Lethathamo (Tafole2) .2). Tlhahisoleseling e felletseng, libaka tsa chromosomal, tatelano e kholo, le maemo a polelo ho CNS ea li-miRNA tsena tse tharo li fumaneha ho Tafole S2 ho Supplementary Material.

Kameho ea Synergistic ea Phetoho e tšoanang ea Li-miRNA tse tharo ho Kotsi ea IGD

Ho lekola phello e kopaneng ea li-miRNA tse tharo, re hlokometse litekanyetso tse sa lumellaneng (li-OR) tsa lihlopha tse 'ne (ka 0, 1, 2, kapa 3 miRNA liphetoho). phetoho ea miRNA e hlalositsoe ke boleng ba RQ joalo ka ha ho hlalositsoe Karolong eaLisebelisoa le mekhoa. ”Hobane matšoao ohle a mararo a maRNA a ne a nyenyefalitsoe sehlopheng sa IGD, miRNA eo boleng ba eona ba RQ bo neng bo le ka tlase ho e 'ngoe e ne e nyenyefalitsoe. Tlhahisoleseling e felletseng ea boleng bo bong le bo bong ba thuto ea RQ bakeng sa li-miRNA tse tharo e fumaneha ho Tafole S3 ho Litšehetso tse Tlatsetsang. Bakeng sa sehlotšoana se seng le se seng, mathata a ne a baloa e le karolelano ea palo ea taolo ho ea li-IGD, ebe OR e 'ngoe le e' ngoe e ne e baloa ka ho arohana le menahano ea sehlotšoana se seng le se seng ka mehopolo ea sehlahana ntle le liphetoho tsa miRNA. Batho ba nang le liphetoho tse tharo tsa miRNA ba bonts'itse kotsi ea linako tsa 22 e phahame ho feta e se nang liphetoho tsa miRNA (OR 22, 95% CI 2.29-211.11). Li-ORs li bontšitse mokhoa o ntseng o eketseha ka palo ea li-miRNA tse fetotsoeng ho tloha 0 ho 3 (r2 = 0.996) (Setšoantšo (Figure22).

Faele e kantle e nang le setšoantšo, papiso, joalo-joalo Lebitso la ntho ke fpsyt-09-00081-g002.jpg
Litekanyetso tsa "Odds" ka palo ea matšoao a nyenyefalitsoeng a microRNA (miRNA). Likhakanyo tsa lintlha tse kaholimo ho litekanyetso ke li-ORs (95% karohano ea ho itšepa).

Tlhahlobo ea GO le ea Pathway ea Target gen ea li-miRNA

Ho fumana leseli la ts'ebetso ea matšoao a miRNA a mararo a theotsoe haholo sehlopheng sa IGD, mefuta ea bona ea sepheo e boletsoe esale pele ba sebelisa database ea miRWalk 2.0 (). Ka kakaretso mefuta ea 1,230 e ne e boletsoe esale pele e le liphofu tse ka tlase ho lefatše ke li-algorithms tse nne (miRWalk, miRanda, RNA22, le Targetscan) ba sebelisa database ea miRWalk (-) (Lethathamo la S4 ho Litšehetso tse Tlatsetsang). Gene e hlophisitse tlhahlobo ea ntlafatso e sebelisa ToppFun ho ToppGene Suite e bontšitse hore mefuta ea sepheo ea li-miRNA tsena e ne e amana haholo le litsela tsa nts'etsopele ea neural joalo ka "Tataiso ea Axon" le mantsoe a GO joalo ka "neurogeneis" (Tafole S5 ho Tlatsetso ea Litaba).

Phatlalatso ea Pono ea Tlhase e boletsoeng esale pele

Har'a mefuta ea sepheo se tlase sa li-miRNA tse tharo, 140 e ile ea boleloa esale pele ka nako e le 'ngoe bakeng sa li-miRNA tse peli kapa ho feta (Tafole S4 ho Supplementary Material). Ho fumana hore na maemo a bona a liprotheine tse tlase tsa mofuta oa sepheo se tlase a fapana joang pakeng tsa IGD le lihlopha tsa taolo, re khethile mefuta ea 2 (DUSP4 'me PI15), tse boletsoeng esale pele e le liphofu tse tlase tsa mefuta eohle ea li-3 miRNA le mefuta e meng ea 3 (GABRB2, DPYSL2, 'me CNR1) ho tsoa ho ba boletsoeng esale pele bakeng sa li-XRUMX miRNA mme ba etsa tlhahlobo ea bophirima ka li-sampuli tsa plasma tse tsoang ho 2 IGDs le li-28 tse laoloang tlhahlobo eo. Re bapisitse polelo ea lipehelo tse hlano lipakeng tsa IGD le lihlopha tsa taolo ka ho lekanya botebo ba sehlopha le sebaka joalo ka ha ho hlalositsoe kae kae (). Har'a tsona, maemo a polelo a DPYSL2 (28 IGD le li-28 control, P = 0.0037) le GABBR2 (li-IGD tsa 27 le taolo ea 28, P = 0.0052) li ne li phahame haholo sehlopheng sa IGD (Setšoantšo (Figure3) .3). Leha ho le joalo, ha re khone ho bona litlhaloso tse fapaneng tsa CNR1 (P = 0.0853), DUSP4 (P = 0.5443), le PI15 (P = 0.6346).

 

Faele e kantle e nang le setšoantšo, papiso, joalo-joalo Lebitso la ntho ke fpsyt-09-00081-g003.jpg

Litšoantšo tsa West blot le mabokose a mabokose a bontšang polelo ea (A) DPYSL2 le (B) GABRB2. Ka bobeli liprotheine tsa DPYSL2 le GABRB2 li bontšitse phapang e kholo maemong a bona a polelo pakeng tsa bothata ba lipapali tsa inthanete (IGD) le sampole tsa taolo (P-ba bohlokoa <0.05). Liprotheine tse peli li hlahisitsoe maemong a holimo mehlala ea IGD.

Puisano

Ho tlalehiloe hore li-miRNA li kentse letsoho kholisong ea neuronal (, ), le polelo e khethollang ea li-miRNA tsa boko li bonoa ho mafu a mafu a kelello a kang schizophrenia (). Ka hona, ho a utloahala hore ho potoloha lifaele tsa miRNA e ka ba li-biomarkers tse sebetsang bakeng sa IGD. LiRNA tsa ho potoloha li khothalelitsoe e le li-biomarkers bakeng sa mathata a mefuta-futa a neuropsychiatric (-); le ha ho le joalo, mekhoa ea limolek'hule ka morao ho nts'etsopele ea IGD e ntse e sa tsejoe haholo leha e le bohlokoa ba eona ba kliniki le ba sechaba. Ka ho khetheha, ha ho na lithuto tse mabapi le li-miRNA tse amanang le IGD. Sepheo sa thuto ena se ne se habeli. Pele, re lekile ho fumana li-plasma miRNA tse amanang le IGD. Taba ea bobeli, re sekasekile moelelo oa tlhaho oa bakuli ba miRNA ka ho hlahloba polelo ea protheine le mofuta oa mefuta ea sepheo se tlase. Ka tlhaiso-leseling e pharalletseng ea li-profiles tsa polelo tsa miRNA le netefatso ea mokoloto oa baitlami, re fumane polelo ea mela e meraro ea liRNA (hsa-miR-200c-3p, hsa-miR-26b-5p, le hsa-miR-652-3p) e tlase haholo ho bakuli ba IGD ho feta taolo. Leha mekhoa ea polelo ea baemeli ba bang ba supileng ba maRNA e ne e sa ngolisoe tlhaisong, e ka ba mpe hampe ka lebaka la sampole e nyane thutong ena. Ho tsebo ea rona, ena ke tlaleho ea pele ea monyetla oa hore li-profil tsa expression tsa miRNA li ka ba li-biomarkers tse ntle bakeng sa IGD. Ho kopantsoe matšoao a miRNA a mararo e ka sebetsa e le sesebelisoa se sa rateheng sa ho khetholla batho ba kotsing ea IGD.

Li-miRNA tse khethiloeng thutong ena ho tlalehiloe hore li kenya letsoho likhethong tse fapaneng tsa neuropsychiatric. Khopolo ea hsa-miR-200c maling e tlalehiloe e le tlase maemong a mangata a mafu a kelello a kang schizophrenia () le likarolo tse kholo tsa khatello ea maikutlo (). miR-200c ho tlalehiloe hore e hlahisitsoe haholo ka likarolo tsa karohano ea synaptic ho feta ho phatloha ka botlalo ea phatla () le ho amana le lefu la lisele tsa neuronal (). Ho ipapisitsoe le litlaleho tsena tse fetileng, miR-200c e kenya letsoho ts'ebetsong ea methapo ea methapo ebile e ka amahanngoa le mathata a neuropsychiatric haeba polelo ea eona e ts'oenyehile. Liphuputso tse 'maloa li khothalelitse setsoalle pakeng tsa miR-652 le kotsi ea ho senyeha ha neuropsychiatric. Ka mokhoa o ts'oanang le mokhoa oa rona, ho khetholla li-biomarkers tsa mali bakeng sa schizophrenia, Lai et al. e entse tlhahlobo ea TLDA le bakuli ba schizophrenia le taolo e tloaelehileng, mme ba fumana hore li-miRNA tse supileng ho kenyeletsa le hsa-miR-652 li bontšitsoe ka mokhoa o fapaneng ho bakuli ba schizophrenia (). Phuputsong e latelang, ba qopile mohlala oa ho noha ba sebelisa datha ea polelo ea miRNA mme ba atlehile ho khetholla schizophrenia taolong e tloaelehileng (). Polelo e fetohileng ea hsa-miR-652 e boetse e bonoe ho lino tse tahang (). Hsa-miR-26b e fumanoe e ts'ebetsong nakong ea phapang ea sele ea neuronal (). Perkins et al. e tlaleha hore hsa-miR-26b e ne e theotsoe ka tlase ho sehlopha sa bakuli ba lefu la kelello (pele ho "cortex")).

Leha ho se na bopaki bo tobileng ba ho tšehetsa kamano lipakeng tsa polelo e nyarosang ea li-miRNA tsena le pathophysiology ea IGD, re ka tseba hore ts'oaetso ea li-miRNA tsena li ka amahanngoa le pathophysiology ea IGD e ipapisitse le litlaleho tse fapaneng tsa pejana mabapi le mefuta e tlase ea meeli eo re e boletseng esale pele . Tse ling tsa mefuta e theohelang tlaase ea li-miRNA tse tharo joalo ka GABRB2, CNR1, NRXN1, 'me DPYSL2 ho tlalehoa hore li amana le mathata a neuropsychiatric. Gamma-aminobutyric acid (GABA) ke "neurotransmitter" e ka sehloohong inhibitory neurotransmitter ho CNS. Ts'isinyeho ea GABA receptor, e ameha mathateng a neuropsychiatric ho kenyelletsa ho lemalla, ho tšoenyeha le khatello ea maikutlo (), tseo hape e leng likarolo tsa mantlha tsa IGD (). Li-polymorphisms tsa liphatsa tsa lefutso tsa GABA receptor li tlalehoa li amana le bokhoba ba joala le schizophrenia (, ). Dihydropyrimidinase-X XUMUM (DPYSL2) ke setho sa lelapa le arabelang ka liprotheine tsa collapsin, se etsang karolo ea kopano ea microtubule, signaptic synaptic, le taolo ea kholo ea axonal. Ka lebaka leo, molek'hule ena e hlahisitsoe e le biomarker bakeng sa mafu a kelello (, ). Polymorphism ho DPYSL2 gene e boetse e tlalehiloe e amana le bokuli ba tšebeliso ea joala (). Litlaleho tsa nakong e fetileng le data ea rona li fana ka maikutlo a hore overexpression ea GABRB2 le DPYSL2, liphofu tse theohileng tsa li-miRNA tse theotsoeng ka tlase, li na le litlamorao ho pathogeneis ea mathata a neuropsychiatric ho kenyelletsa IGD. Cannabinoid receptor mofuta 1 (CNR1) ke presynaptic heteroreceptor e fetolang tokollo ea li-neurotransmitter le likhathatso tsa ho saena hoa cannabinoid li amahanngoa le mathata a fapaneng a neuropsychiatric (). Polymorphism ea liphatsa tsa lefutso ea CNR1 gene e tsejoa e amahanngoa le ts'ebeliso ea ts'ebeliso ea thepa ho Caucasians (). Ka mohlala oa rat, ts'ebetso ea "ventral hippocampus CNR1" e senya boitšoaro bo tloaelehileng ba sechaba le ho utloisisa (). Ho fetoha hoa liphatsa tsa lefutso lelapeng la NRXN ho tsejoa ho kenya letsoho likhethong tse fapaneng tsa neuropsychiatric ho kenyeletsa le ho lemalla ().

Ho hlahloba bohlokoa ba likokoana-hloko tsa baemeli ba bararo ba maRNA ka tsela e otlolohileng, re ile ra hlahloba polelo ea protheine ea mefuta ea bona e tlase. Ka lebaka la phokotso e lekanyelitsoeng ea sampole ea plasma, ea baeti ba tloaelehileng ba 140 (ba boletsoeng esale pele e le tlase ho 2 kapa li-miRNA tse ngata), re ile ra hlahloba lipehelo tsa 5 (GABRB2, DPYSL2, CNR1, DUSP4, le PI15) ka polelo ea GNBX le ho netefalitsoe ka GNUMX. mme DPYSL2 e ne e phahame haholo sehlopheng sa IGD. Litlaleho tsa nakong e fetileng le data ea rona li fana ka maikutlo a hore oxprexpression ea GABRB2 le DPYSL2, liphofu tse theohileng tsa li-miRNA tse theotsoeng ka tlase, li ka ba le litlamorao ho pathogeneis ea mathata a neuropsychiatric ho kenyelletsa IGD. Liphetho tsa tlhahlobo ea 'mele ea "GO" le tsela ea mekhoa ea nts'etsopele ea neural e ts'ehetsa maikutlo a methapo ea methapo ea miRNA. Sephetho se seng se khahlisang e bile phello ea ho kopanya ka nako e le 'ngoe ha li-miRNAs. Batho ba nang le phallo e tlase ea li-maRNA tsohle tsa 2 ba bonts'itse likotsi tsa 3 makhetlo a mangata ho feta tse se nang tlhatlhobo, mme li-OR li ile tsa eketseha ka tsela e itšetlehileng ka tekanyetso. Leha CI bakeng sa liphetoho tsena tse tharo e ne e le kholo ka lebaka la sampole e fokolang, phumano e hlakileng e hlakileng (r2 = 0.996) e ts'ehetsa phello e lumellanang ea li-miRNA tse tharo.

Le ha re fumane matšoao a amanang le IGR a amanang le li-IGD le batho ka bomong ba nang le liphetoho tse tharo tsa miRNA ba ne ba le kotsi ea linako tsa 22 e phahame ho feta tse se nang phetoho ea miRNA, ho na le meeli e 'maloa thutong ena. Taba ea pele, sampole e nyane e ile ea eketsa menyetla ea ho lahleheloa ke matšoao a mang a bohlokoa a MiRNA. Taba ea bobeli, kaha data ea rona e ne e sa lekana ho hlakisa hore na lifaele tsa plasma miRNA li bakoa kapa li na le phello, re ke ke ra netefatsa likarolo tsa baeloji ba matšoao ana a sa hlaseleng tikolohong ea bongaka. Ho fana ka likarabo tse ling tse ntlafalitsoeng ka tlhaiso-leseling ea micRNA le tlhahlobo ea bona ea liphatsa tsa lefutso tse sebelisang methapo ea kelello ea motho ho tsoa bankeng ea lisele tsa boko li ka fana ka karabo e hlakileng haholoanyane. Ho hlahlojoa ha lisele tsa bori le mofuta oa phoofolo ea bolo ea maoto le hona ho ka ba molemo. Taba ea boraro, ka lebaka la khaello e lekanyelitsoeng ea disampole tsa plasma, re ile ra hlahloba limolek'hule tse hlano feela tsa batho ba tlase. Ho hlahloba sepheo se tlase sa ho theoha ka sampole e kholo ho tla thusa ho utloisisa mochine oa molek'hule oa IGD.

Ka kakaretso, ka tlhaiso-leseling e pharalletseng ea profil expression ea miRNA le netefatso e ikemetseng, re fumane li-miRNA tse tharo tse amanang le IGD (hsa-miR-200c-3p, hsa-miR-26b-5p, le hsa-miR-652-3p). Bongata ba mefuta ea bona e theohelang tlase ho tlalehoa e khathetse mefuteng e fapaneng ea methapo ea methapo, mme tlhahlobo ea netefatso ea polelo e fetotsoeng ea mefuta ena e tlase e ts'ehetsa moelelo oa li-miRNA tse khethiloeng thutong ena. Re fumane hore batho ba nang le tlase ka tlase ho li-miRNA tsohle tse tharo ba kotsing e kholo ea IGD. Hammoho le lintlha tse tsebahalang tsa kliniki kapa tikoloho le mekhoa ea tlhahlobo, liphumano tsa rona li ka tsamaisa ts'ebetso ea pele ho thusa batho ba kotsing e kholo ea IGD.

Boitšoaro ba Melao

Boithuto bona bo amohetsoe ke Institutional Review Board ea Katolike University Medical Medical of Korea (MC16SISI0120). Barupeluoa bohle le batsoali ba bona ba fane ka tumello e ngotsoeng.

Menehelo ea Mongoli

ML le HC ba kentse letsoho ka mokhoa o tšoanang pampiring ena. ML, D-JK, le Y-JC ba qapile thuto. SJ, S-MC, YP, DC, le JL li entse liteko le tlhaiso-leseling. J-WC, S-HP, J-SC, le D-JK ba bokelletse sampole ea mali le tlhaiso-leseling ea bongaka. ML, HC, S-HY, le Y-JC ba hlahlobisitse tlhaiso-leseling. ML, HC, S-HY, le Y-JC ba hlalositse mongolo. Y-JC e hlokometse morero.

Tlhōlisano ea Tlhaloso

Bangoli ba bolela hore lipatlisiso li ne li etsoa ka ho se be le likamano leha e le life tsa khoebo kapa tsa lichelete tse ka nkoang e le khohlano e ka 'nang ea e-ba le thahasello.

Mongolo o botlaaseng ba leqephe

 

Lithuso. Mosebetsi ona o tšehelitsoe ke chelete e tsoang ho Lenaneo la Lipatlisiso la Brain ka National Research Foundation ea Korea (NRF), e tšehelitsoeng ke Lefapha la Mahlale le ICT le Tlhophiso ea Bokamoso (NRF-2015M3C7A1064778).

 

 

Boitsebiso bo Eketsehileng

Lintho tse tlatsetsang bakeng sa sengoloa sena li ka fumaneha inthaneteng ho http://www.frontiersin.org/articles/10.3389/fpsyt.2018.00081/full#supplementary-material.

References

1. Mocha KS. Tlatsetso ea inthanete: ho hlaha ha bokuli bo bocha ba kliniki. Cyber ​​Psychol Behav (1998) 1 (3): 237-44.10.1089 / cpb.1998.1.237 [Ref Ref Cross]
2. Petry NM, Rehbein F, Ko CH, O'Brien CP. Bothata ba lipapali tsa inthanete ho DSM-5. Curr Psychiatry Rep (2015) 17 (9): 72.10.1007 / s11920-015-0610-0 [E fetotsoe] [Ref Ref Cross]
3. Cho H, Kwon M, Choi JH, Lee SK, Choi JS, Choi SW, et al. Nts'etsopele ea sekhahla sa ts'ebeliso ea litheko tsa inthanete e thehiloeng ho mekhoa ea ho bapatsa papali ea marang-rang e khothalelitsoeng ho DSM-5. Addict Behav (2014) 39 (9): 1361-6.10.1016 / j.addbeh.2014.01.020 [E fetotsoe] [Ref Ref Cross]
4. Kuss DJ, Griffiths MD, Karila L, Billieux J. Tlatsetso ea marang-rang: tlhahlobo e hlophisitsoeng ea lipatlisiso tsa mafu a seoa lilemong tse leshome tse fetileng. Curr Pharm Des (2014) 20 (25): 4026-52.10.2174 / 13816128113199990617 [E fetotsoe] [Ref Ref Cross]
5. Park M, Choi JS, Park SM, Lee JY, Jung HY, Sohn BK, et al. Ts'ebetso ea tlhaiso-leseling ea ts'ebetso nakong ea tlhahlobo ea liketsahalo tse amanang le liketsahalo ho batho ba nang le bothata ba lipapali tsa inthanete. Translate Psychiatry (2016) 6: e721.10.1038 / tp.2015.215 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
6. Lim JA, Lee JY, Jung HY, Sohn BK, Choi SW, Kim YJ, et al. Liphetoho tsa boleng ba bophelo le ts'ebetso ea kelello ho batho ba nang le bothata ba lipapali tsa inthanete: ho lateloa ha khoeli ea 6. Bongaka (Baltimore) (2016) 95 (50): e5695.10.1097 / MD.0000000000005695 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
7. van Rooij AJ, Van Looy J, Billieux J. Lits'oaetso tsa lipapali tsa inthanete e le sebopeho se hlophisitsoeng: litlamorao bakeng sa conceptualization le tekanyo. Psinchiatry Clin Neurosci (2016) 71 (7): 445-58.10.1111 / pcn.12404 [E fetotsoe] [Ref Ref Cross]
8. Mokhatlo oa American Psychiatric Association, mohlophisi. , mohlophisi. Buka ea Tlhahlobo le Tlaleho ea Bofokoli ba Kelello: DSM-5. 5th ed Arlington, VA: Mokhatlo oa Amerika oa Psychiatric; (2013).
9. Vink JM, van Beijsterveldt TC, Huppertz C, Bartels M, Boomsma DI. Heritility ea ts'ebeliso e qobelloang ea inthanete ho bacha. Addict Biol (2016) 21 (2): 460-8.10.1111 / adb.12218 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
10. Li M, Chen J, Li N, Li X. Patlisiso e entsoeng ka bobeli ea tšebeliso ea marang-rang e nang le bothata: heritility le mokhatlo oa liphatsa tsa lefutso ka taolo e sebetsang. Twin Res Hum Genet (2014) 17 (4): 279-87.10.1017 / thg.2014.32 [E fetotsoe] [Ref Ref Cross]
11. Han DH, Lee YS, Yang KC, Kim EY, Lyoo IK, Renshaw PF. Dopamine liphatsa tsa lefutso le ho itšetleha ka moputso ho bacha ba nang le papali ea video e fetelletseng ea inthanete. J Addict Med (2007) 1 (3): 133-8.10.1097 / ADM.0b013e31811f465f [E fetotsoe] [Ref Ref Cross]
12. Lee YS, Han DH, Yang KC, Daniels MA, Na C, Kee BS, et al. Ho sithabela maikutlo joalo ka litšobotsi tsa 5HTTLPR polymorphism le bohale ho basebelisi ba fetelletseng ba marang-rang. J Afimate Disord (2008) 109 (1-2): 165-9.10.1016 / j.jad.2007.10.020 [E fetotsoe] [Ref Ref Cross]
13. Montag C, Kirsch P, Sauer C, Markett S, Reuter M. Karolo ea mofuta oa CHRNA4 tlatsetsong ea ho lemalla inthanete: thuto ea taolo ea linyeoe. J Addict Med (2012) 6 (3): 191-5.10.1097 / ADM.0b013e31825ba7e7 [E fetotsoe] [Ref Ref Cross]
14. Kim JY, Jeong JE, Rhee JK, Cho H, Chun JW, Kim TM, et al. Thulaganyo e lebelletsoeng ea ho bonts'a phapang e sirelletsang khahlanong le ts'oaetso ea lipapali tsa inthanete ho rs2229910 ea neurotrophic tyrosine kinase receptor, mofuta 3 (NTRK3): thuto ea sefofane. J Behav Addict (2016) 5 (4): 631-8.10.1556 / 2006.5.2016.077 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
15. Issler O, Chen A. Ho khetholla karolo ea li-microRNA maemong a mafu a kelello. Nat Rev Neurosci (2015) 16 (4): 201-12.10.1038 / nrn3879 [E fetotsoe] [Ref Ref Cross]
16. Kocerha J, Dwivedi Y, Brennand KJ. Li-RNA tse sa koaheleng le mekhoa ea ho sebetsana le mafu a kelello. Mol Psychiatry (2015) 20 (6): 677-84.10.1038 / mp.2015.30 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
17. Ambros V. MicroRNA: batsamaisi ba melao e nyane ba nang le bokhoni bo boholo. Cell (2001) 107 (7): 823-6.10.1016 / S0092-8674 (01) 00616-X [E fetotsoe] [Ref Ref Cross]
18. Hollins SL, Cairns MJ. MicroRNA: babuelli ba fokolang ba RNA ba karabo genomic ho khatello ea tikoloho. Prog Neurobiol (2016) 143: 61-81.10.1016 / j.pneurobio.2016.06.005 [E fetotsoe] [Ref Ref Cross]
19. Lopez JP, Lim R, Cruceanu C, Crapper L, Fasano C, Labonte B, et al. miR-1202 ke microRNA e ikhethang e ikhethileng ebile e ntlafalitsoe ke ts'ebeliso ea maikutlo le khatello e kholo ea maikutlo le khatello ea maikutlo. Nat Med (2014) 20 (7): 764-8.10.1038 / nm.3582 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
20. Kim YS, Cheon KA, Kim BN, Chang SA, Yoo HJ, Kim JW, et al. Ho ts'epahala le ho nepahala ha kemiso ea bana bakeng sa mathata a amanang le mathata a amanang le mathata a bophelo bo botle le thuto ea maikutlo ea sejoale-joale le bophelo ba mofuta oa bophelo ba mofuta oa bophelo ba Korea. (K-SADS-PL-K). Yonsei Med J (2004) 45 (1): 81-9.10.3349 / ymj.2004.45.1.81 [E fetotsoe] [Ref Ref Cross]
21. Kwak K, Oh S, Kim C. Manual for Korea Wechsler Intelligence Scale for Children-IV (K-WISC-IV) -Manual. Seoul, Korea Boroa: Hakjisa; (2011).
22. Patton JH, Stanford MS, Barratt ES. Sebopeho sa lintlha tsa Barratt Impulsiveness Scale. J Clin Psychol (1995) 51 (6): 768-74.10.1002 / 1097-4679 (199511) 51: 6 <768 :: AID-JCLP2270510607> 3.0.CO; 2-1 [E fetotsoe] [Ref Ref Cross]
23. Carver C, TL e tšoeu. Ho thibela boitsoaro, ts'ebetso ea ts'ebetso, le likarabo tse amanang le moputso le kotlo e tlang: sekala sa BIS / BAS. J Pers Soc Psychol (1994) 67 (2): 319-33.10.1037 // 0022-3514.67.2.319 [Ref Ref Cross]
24. Weiland M, Gao XH, Zhou L, Mi QS. Li-RNA tse nyane li na le tšusumetso e kholo: ho potoloha li-microRNA e le li-biomarkers bakeng sa maloetse a batho. RNA Biol (2012) 9 (6): 850-9.10.4161 / rna.20378 [E fetotsoe] [Ref Ref Cross]
25. Dvinge H, Bertone P. HTqPCR: tlhaiso-leseling e kholo ea tlhaiso-leseling ea nako ea sebele ea PCR ho R. Bioinformatics (2009) 25 (24): 3325-6.10.1093 / bioinformatics / btp578 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
26. Leek JT, Storey JD. Ho ts'oara heterogeneity lithutong tsa polelo ea liphatsa tsa lefutso ka tlhahlobo e fapaneng ea surrogate. PloS Genet (2007) 3 (9): 1724-35.10.1371 / journal.pgen.0030161 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
27. Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene suite bakeng sa tlhahlobo ea ntlafatso ea lenane le tlhahlobo ea mantlha ea setho. Nucleic Acids Res (2009) 37 (Taba ea Web Server): W305-11.10.1093 / nar / gkp427 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
28. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: sesebelisoa sa ho kopanya biology. Gene ontology Consortium. Nat Genet (2000) 25 (1): 25-9.10.1038 / 75556 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
29. Cheon DH, Nam EJ, Park KH, Woo SJ, Lee HJ, Kim HC, et al. Tlhahlobo e felletseng ea protheine ea motho ea boima ba limolek'hule tse tlase tse sebelisang matla a maholohali a 'mele. J Proteome Res (2016) 15 (1): 229-44.10.1021 / acs.jproteome.5b00773 [E fetotsoe] [Ref Ref Cross]
30. Park CH, Chun JW, Cho H, Jung YC, Choi J, Kim DJ. Na boko bo lemaletseng papali ea marang-rang bo haufi le ho ba maemong a phelisang? Addict Biol (2017) 22 (1): 196-205.10.1111 / adb.12282 [E fetotsoe] [Ref Ref Cross]
31. Dweep H, Gretz N. miRWalk2.0: sebaka se pharaletseng sa tšebelisano-hloko ea microRNA. Mekhoa ea Nat (2015) 12 (8): 697.10.1038 / nmeth.3485 [E fetotsoe] [Ref Ref Cross]
32. Enright AJ, John B, Gaul U, Tuschl T, Sander C, Marea DS. Sepheo sa MicroRNA ka Drosophila. Genome Biol (2003) 5 (1): R1.10.1186 / gb-2003-5-1-r1 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
33. Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, et al. Mokhoa o thehiloeng hodima mohlala bakeng sa ho khetholla libaka tse tlamang tsa MicroRNA le li-heteroduplexes tse tsamaellanang. Sele (2006) 126 (6): 1203-17.10.1016 / j.cell.2006.07.031 [E fetotsoe] [Ref Ref Cross]
34. Lewis BP, Burge CB, Bartel DP. Ho tsamaisoa ha peo e bolokiloeng, hangata e ts'oaroang ke adenosine, ho bontša hore mefuta e likete ea batho ke liphofu tsa microRNA. Sele (2005) 120 (1): 15-20.10.1016 / j.cell.2004.12.035 [E fetotsoe] [Ref Ref Cross]
35. Schratt GM, Tuezing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, et al. MicroRNA e tobileng ea boko e laola nts'etsopele ea mokokotlo oa dendritic. Tlhaho (2006) 439 (7074): 283-9.10.1038 / nature04367 [E fetotsoe] [Ref Ref Cross]
36. Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V. Ho hlahisa maikutlo ka li-microRNA tsa mammogo ho sibolla sephutheloana sa li-microRNA tse hlahisitsoeng ke boko ka likarolo tse ka khonehang molekong le karohanong ea methapo ea motho. Genome Biol (2004) 5 (3): R13.10.1186 / gb-2004-5-3-r13 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
37. Beveridge NJ, Tooney PA, Carroll AP, Gardiner E, Bowden N, Scott RJ, et al. Ts'oaetso ea miRNA 181b sebakeng sa "cortex" sa nakoana ka "schizophrenia". Hum Mol Genet (2008) 17 (8): 1156-68.10.1093 / hmg / ddn005 [E fetotsoe] [Ref Ref Cross]
38. Wei H, Yuan Y, Liu S, Wang C, Yang F, Lu Z, et al. Ho fumanoa ha lipalo tsa miRNA tse potolohang ho schizophrenia. Am J Psychiatry (2015) 172 (11): 1141-7.10.1176 / appi.ajp.2015.14030273 [E fetotsoe] [Ref Ref Cross]
39. Dwivedi Y. Pathogenetic le kalafo ea ts'ebeliso ea li-microRNA maemong a maholo a sithabetsang. Prog Neuropsychopharmacol Biol Psychiatry (2016) 64: 341-8.10.1016 / j.pnpbp.2015.02.003 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
40. Hara N, Kikuchi M, Miyashita A, Hatsuta H, Saito Y, Kasuga K, et al. Serum microRNA miR-501-3p e le biomarker e ka bang teng e amanang le lefu la lefu la Alzheimer's. Acta Neuropathol Commun (2017) 5 (1): 10.10.1186 / s40478-017-0414-z [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
41. Gardiner E, Beveridge NJ, Wu JQ, Carr V, Scott RJ, Tooney PA, et al. Sebaka se profetiloeng sa DLK1-DIO3 sa 14q32 se hlalosa signature ea li-miRNA e amanang le schizophrenia liseleng tsa mali tsa nyutlelie ea mononuclear. Mol Psychiatry (2012) 17 (8): 827-40.10.1038 / mp.2011.78 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
42. Belzeaux R, Bergon A, Jeanjean V, Loriod B, Formisano-Treziny C, Verrier L, et al. Bakuli ba arabelang le ba sa tsamaisane le bona ba bontša matšoao a sa tšoaneng a ho ngola a tšoaeang nakong ea ketsahalo e kholo ea khatello. Translate Psychiatry (2012) 2: e185.10.1038 / tp.2012.112 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
43. Lugli G, Torvik VI, Larson J, Smalheiser NR. Pontšo ea li-microRNA le tse e tlang pele ho tsona likaroloana tsa methapo ea kutlo ea motho e moholo. J Neurochem (2008) 106 (2): 650-61.10.1111 / j.1471-4159.2008.05413.x [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
44. Stary CM, Xu L, Sun X, Ouyang YB, White RE, Leong J, et al. MicroRNA-200c e kenya letsoho ho tsoa likotsi tse tsoang ho ischemia ea nakoana ea kelello e bakoang ke reelin. Stroke (2015) 46 (2): 551-6.10.1161 / STROKEAHA.114.007041 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
45. Lai CY, Yu SL, Hsieh MH, Chen CH, Chen HY, Wen CC, et al. Phallo ea polelo ea MicroRNA e le li-biomarkers tsa mali tse ka bang paripheral bakeng sa schizophrenia. PloS One (2011) 6 (6): e21635.10.1371 / journal.pone.0021635 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
46. Lai CY, Lee SY, Scarr E, Yu YH, Lin YT, Liu CM, et al. Polelo e nyarosang ea li-microRNA e le biomarker bakeng sa schizophrenia: ho tloha boemong bo sisimosang ho isa ho a sa feleng a mali, le ho tsoa maling a pherekano ho isa ho lithane tsa cortical. Translate Psychiatry (2016) 6: e717.10.1038 / tp.2015.213 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
47. Lewohl JM, Nunez YO, Dodd PR, Tiwari GR, Harris RA, Mayfield RD. Tlhahiso-leseling ea li-microRNA kelellong ea batho ba tahi. Alcohol Clin Exp Res (2011) 35 (11): 1928-37.10.1111 / j.1530-0277.2011.01544.x [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
48. Dill H, Linder B, Fehr A, Fischer U. Intronic miR-26b e laola phapang ea li-neuronal ka ho hatisa mongolo oa eona oa ho amohela, ctdsp2. GMD (2012) 26 (1): 25-30.10.1101 / gad.177774.111 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
49. Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, et al. Polelo ea MicroRNA ka pele ho cortex ea batho ba nang le lefu la kelello le lefu la kelello. Genome Biol (2007) 8 (2): R27.10.1186 / gb-2007-8-2-r27 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
50. Kumar K, Sharma S, Kumar P, Deshmukh R. Therapeutic bokhoni ba GABA (B) li-receptor ligands ho ts'ebeliso ea lithethefatsi, ho tšoenyeha, khatello ea maikutlo le mathata a mang a CNS. Pharmacol Biochem Behav (2013) 110: 174-84.10.1016 / j.pbb.2013.07.003 [E fetotsoe] [Ref Ref Cross]
51. McCracken ML, Borghese CM, Trudell JR, Harris RA. A transmembrane amino acid ho GABAA receptor beta2 subunit e bohlokoa bakeng sa liketso tsa alcohols le anesthetics. J Pharmacol Exp Ther (2010) 335 (3): 600-6.10.1124 / jpet.110.170472 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
52. Zong L, Zhou L, Hou Y, Zhang L, Jiang W, Zhang W, et al. Melao ea liphatsa tsa lefutso le epigenetic mabapi le phetisetso ea GABRB2: liphetoho tse itšetlehileng ka genotype le hydroxymethylation le methylation ho schizophrenia. J Psychiatr Res (2017) 88: 9-17.10.1016 / j.jpsychires.2016.12.019 [E fetotsoe] [Ref Ref Cross]
53. Fukata Y, Itoh TJ, Kimura T, Menager C, Nishimura T, Shiromizu T, et al. CRMP-2 e tlama ho tubulin heterodimers ho khothaletsa kopano ea microtubule. Nat Cell Biol (2002) 4 (8): 583-91.10.1038 / ncb825 [E fetotsoe] [Ref Ref Cross]
54. Kekesi KA, Juhasz G, Simor A, Gulyassy P, Szego EM, Hunyadi-Gulyas E, et al. E fetotsoe marang-rang a sebetsang a liprotheine ho cortex ea pele le amygdala ea bahlaseluoa ba ho ipolaea. PloS One (2012) 7 (12): e50532.10.1371 / journal.pone.0050532 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
55. Taylor A, Wang KS. Kopano lipakeng tsa DPYSL2 gene polymorphisms le ts'ehetso ea joala lits'ebetsong tsa Caucasian. J Neural Transm (Vienna) (2014) 121 (1): 105-11.10.1007 / s00702-013-1065-2 [E fetotsoe] [Ref Ref Cross]
56. Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, et al. Sebopeho sa Crystal sa cannabinoid receptor CB1. Sele (2016) 167 (3): 750-62.e14.10.1016 / j.cell.2016.10.004 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
57. Benyamina A, Kebir O, Blecha L, Reynaud M, Krebs MO. Li-polymorphisms tsa genR1 tsa mafu a tlatsetsang: tlhahlobo e hlophisehileng le tlhahlobo ea meta. Addict Biol (2011) 16 (1): 1-6.10.1111 / j.1369-1600.2009.00198.x [E fetotsoe] [Ref Ref Cross]
58. Loureiro M, Kramar C, Renard J, Rosen LG, Laviolette SR. Phetisetso ea "cannabinoid" ka hippocampus activates li-neurons mme modulates moputso le ho hloleha ha maikutlo ho amanang le ho hlohlona. Biol Psychiatry (2016) 80 (3): 216-25.10.1016 / j.biopsych.2015.10.016 [E fetotsoe] [Ref Ref Cross]
59. Kasem E, Kurihara T, Tabuchi K. Neurexins le mathata a amanang le neuropsychiatric. Neurosci Res (2017) 127: 53-60.10.1016 / j.neures.2017.10.012 [E fetotsoe] [Ref Ref Cross]