Restricted accessResearch articleFirst published online 2021-8
Association of Gene Variations in Ionotropic Glutamate Receptor and Attention-Deficit/Hyperactivity Disorder in the Chinese Population: A Two-Stage Case–Control Study
Objective: The aim of this study was to comprehensively explore the relationship between genetic variations within GRIN2A, GRIN2B, GRIK1, GRIK4, GRID2, and ADHD. Method: Genotyping was performed with the Sequenom MassARRAY system in a two-stage case–control study. ADHD symptoms were assessed using the Swanson, Nolan, and Pelham version IV scale and the Integrated Visual and Auditory Continuous Performance Test. In silico analysis was performed with website resources. Results: GRID2 rs1385405 showed a significant association with ADHD risk in the codominant model (OR = 2.208, 95% CI = [1.387, 3.515]) in the first stage and in the codominant model (OR = 1.874, 95% CI = [1.225, 2.869]) and recessive model (OR = 1.906, 95% CI = [1.265, 2.873]) in the second stage and related to inattention and hyperactivity symptom. In addition, rs1385405 disturbed the activity of exonic splicing enhancer and mediated GRID2 gene expression in the frontal cortex. Conclusion: our data provided evidence for the participation of GRID2 variants in conferring the risk of ADHD.
AliZ.ZulfiqarS.KlarJ.WikstromJ.UllahF.KhanA.. . . DahlN. (2017). Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features. BMC Medical Genetics, 18(1), Article 144. https://doi.org/10.1186/s12881-017-0504-6
2.
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.).
3.
AshersonP.BuitelaarJ.FaraoneS. V.RohdeL. A. (2016). Adult attention-deficit hyperactivity disorder: Key conceptual issues. The Lancet Psychiatry, 3(6), 568–578. https://doi.org/10.1016/s2215-0366(16)30032-3
4.
BauerJ.WernerA.KohlW.KugelH.ShushakovaA.PedersenA.OhrmannP. (2018). Hyperactivity and impulsivity in adult attention-deficit/hyperactivity disorder is related to glutamatergic dysfunction in the anterior cingulate cortex. World Journal of Biological Psychiatry, 19(7), 538–546. https://doi.org/10.1080/15622975.2016.1262060
ChangC.SiaoS. W. (2016). Cerebellar cognitive affective syndrome: Attention deficit-hyperactivity disorder episode of adolescent with cerebellar atrophy in a psychiatric ward. The Kaohsiung Journal of Medical Sciences, 32(1), 52–54. https://doi.org/10.1016/j.kjms.2015.10.006
7.
ChangJ. P.LaneH. Y.TsaiG. E. (2014). Attention deficit hyperactivity disorder and N-methyl-D-aspartate (NMDA) dysregulation. Current Pharmaceutical Design, 20(32), 5180–5185. https://doi.org/10.2174/1381612819666140110115227
8.
ChengJ.LiuA.ShiM. Y.YanZ. (2017). Disrupted glutamatergic transmission in prefrontal cortex contributes to behavioral abnormality in an animal model of ADHD. Neuropsychopharmacology, 42(10), 2096–2104. https://doi.org/10.1038/npp.2017.30
9.
CostaD. S.de PaulaJ. J.Malloy-DinizL. F.Romano-SilvaM. A.MirandaD. M. (2019). Parent SNAP-IV rating of attention-deficit/hyperactivity disorder: Accuracy in a clinical sample of ADHD, validity, and reliability in a Brazilian sample. Jornal de Pediatria, 95, 736–743. https://doi.org/10.1016/j.jped.2018.06.014
10.
DangL. C.Samanez-LarkinG. R.YoungJ. S.CowanR. L.KesslerR. M.ZaldD. H. (2016). Caudate asymmetry is related to attentional impulsivity and an objective measure of ADHD-like attentional problems in healthy adults. Brain Structure & Function, 221(1), 277–286. https://doi.org/10.1007/s00429-014-0906-6
11.
DasBanerjeeT.MiddletonF. A.BergerD. F.LombardoJ. P.SagvoldenT.FaraoneS. V. (2008). A comparison of molecular alterations in environmental and genetic rat models of ADHD: A pilot study. American Journal of Medical Genetics: Part B, Neuropsychiatric Genetics, 147B(8), 1554–1563. https://doi.org/10.1002/ajmg.b.30877
12.
Dela PeñaI.BangM.LeeJ.de la PeñaJ. B.KimB. N.HanD. H.. . . CheongJ. H. (2015). Common prefrontal cortical gene expression profiles between adolescent SHR/NCrl and WKY/NCrl rats which showed inattention behavior. Behavioural Brain Research, 291, 268–276. https://doi.org/10.1016/j.bbr.2015.05.012
13.
DemontisD.WaltersR. K.MartinJ.MattheisenM.AlsT. D.AgerboE.. . . NealeB. M. (2019). Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics, 51(1), 63–75. https://doi.org/10.1038/s41588-018-0269-7
14.
DianaM. C.SantoroM. L.XavierG.SantosC. M.SpindolaL. N.MorettiP. N.. . .BelangeroS. I. (2015). Low expression of Gria1 and Grin1 glutamate receptors in the nucleus accumbens of Spontaneously Hypertensive Rats (SHR). Psychiatry Research, 229(3), 690–694. https://doi.org/10.1016/j.psychres.2015.08.021
15.
DorvalK. M.WiggK. G.CrosbieJ.TannockR.KennedyJ. L.IckowiczA.. . . BarrC. L. (2007). Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder. Genes, Brain and Behavior, 6(5), 444–452. https://doi.org/10.1111/j.1601-183X.2006.00273.x
16.
EndeG.CackowskiS.Van EijkJ.SackM.DemirakcaT.KleindienstN.. . . SchmahlC. (2016). Impulsivity and aggression in female BPD and ADHD patients: Association with ACC glutamate and GABA concentrations. Neuropsychopharmacology, 41(2), 410–418. https://doi.org/10.1038/npp.2015.153
17.
FanZ.QianY.LuQ.WangY.ChangS.YangL. (2018). DLGAP1 and NMDA receptor-associated postsynaptic density protein genes influence executive function in attention deficit hyperactivity disorder. Brain and Behavior, 8(2), e00914. https://doi.org/10.1002/brb3.914
GadowK. D.ArnoldL. E.MolinaB. S.FindlingR. L.BuksteinO. G.BrownN. V.. . . AmanM. G. (2014). Risperidone added to parent training and stimulant medication: Effects on attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and peer aggression. Journal of the American Academy of Child & Adolescent Psychiatry, 53(9), 948–959.e1. https://doi.org/10.1016/j.jaac.2014.05.008
20.
GalloE. F.PosnerJ. (2016). Moving towards causality in attention-deficit hyperactivity disorder: Overview of neural and genetic mechanisms. The Lancet Psychiatry, 3(6), 555–567. https://doi.org/10.1016/s2215-0366(16)00096-1
21.
GizerI. R.FicksC.WaldmanI. D. (2009). Candidate gene studies of ADHD: A meta-analytic review. Human Genetics, 126(1), 51–90. https://doi.org/10.1007/s00439-009-0694-x
22.
GoetzM.SchwabovaJ.HlavkaZ.PtacekR.ZumrovaA.HortV.DoyleR. (2017). Cerebellar symptoms are associated with omission errors and variability of response time in children With ADHD. Journal of Attention Disorders, 21(3), 190–199. https://doi.org/10.1177/1087054713517745
23.
GreenwoodT. A.LazzeroniL. C.CalkinsM. E.FreedmanR.GreenM. F.GurR. E.. . .BraffD. L. (2016). Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study. Schizophrenia Research, 170(1), 30–40. https://doi.org/10.1016/j.schres.2015.11.008
24.
GuX.YuanF. F.HuangX.HouY.WangM.LinJ.WuJ. (2018). Association of PIK3CG gene polymorphisms with attention-deficit/hyperactivity disorder: A case-control study. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 81, 169–177. https://doi.org/10.1016/j.pnpbp.2017.10.020
25.
HinneyA.ScheragA.JarickI.AlbayrakO.PutterC.PechlivanisS.. . . HebebrandJ. (2011). Genome-wide association study in German patients with attention deficit/hyperactivity disorder. American Journal of Medical Genetics: Part B Neuropsychiatric Genetics, 156B(8), 888–897. https://doi.org/10.1002/ajmg.b.31246
26.
HoogmanM.BraltenJ.HibarD. P.MennesM.ZwiersM. P.SchwerenL. S. J.. . . FrankeB. (2017). Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: A cross-sectional mega-analysis. Lancet Psychiatry, 4(4), 310–319. https://doi.org/10.1016/s2215-0366(17)30049-4
27.
HoogmanM.MuetzelR.GuimaraesJ. P.ShumskayaE.MennesM.ZwiersM. P.. . . FrankeB. (2019). Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples. Am J Psychiatry, 176(7), 531–542. https://doi.org/10.1176/appi.ajp.2019.18091033
28.
HuangX.WangM.ZhangQ.ChenX.WuJ. (2019). The role of glutamate receptors in attention-deficit/hyperactivity disorder: From physiology to disease. American Journal of Medical Genetics: Part B Neuropsychiatric Genetics, 180(4), 272–286. https://doi.org/10.1002/ajmg.b.32726
29.
JerominA.HuganirR. L.LindenD. J. (1996). Suppression of the glutamate receptor delta 2 subunit produces a specific impairment in cerebellar long-term depression. Journal of Neurophysiology, 76(5), 3578–3583. https://doi.org/10.1152/jn.1996.76.5.3578
30.
KakegawaW.MiyazakiT.EmiK.MatsudaK.KohdaK.MotohashiJ.. . . YuzakiM. (2008). Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRdelta2. Journal of Neuroscience, 28(6), 1460–1468. https://doi.org/10.1523/jneurosci.2553-07.2008
31.
KalkanZ.DurasiI. M.SezermanU.Atasever-ArslanB. (2016). Potential of GRID2 receptor gene for preventing TNF-induced neurodegeneration in autism. Neuroscience Letters, 620, 62–69. https://doi.org/10.1016/j.neulet.2016.03.043
32.
KashiwabuchiN.IkedaK.ArakiK.HiranoT.ShibukiK.TakayamaC.. . .MishinaM. (1995). Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR delta 2 mutant mice. Cell, 81(2), 245–252. https://doi.org/10.1016/0092-8674(95)90334-8
33.
KhramtsovaE. A.HeldmanR.DerksE. M.YuD.DavisL. K.StrangerB. E. (2019). Sex differences in the genetic architecture of obsessive-compulsive disorder. American Journal of Medical Genetics: Part B Neuropsychiatric Genetics, 180(6), 351–364. https://doi.org/10.1002/ajmg.b.32687
34.
KimJ. I.KimJ. W.ParkJ. E.ParkS.HongS. B.HanD. H.. . . KimB. N. (2017). Association of the GRIN2B rs2284411 polymorphism with methylphenidate response in attention-deficit/hyperactivity disorder. Journal of Psychopharmacology, 31(8), 1070–1077. https://doi.org/10.1177/0269881116667707
35.
KimJ. I.KimJ. W.ParkS.HongS. B.LeeD. S.PaekS. H.. . . KimB. N. (2016). The GRIN2B and GRIN2A gene variants are associated with continuous performance test variables in ADHD. Journal of Attention Disorders. https://doi.org/10.1177/1087054716649665
36.
KumagaiA.FujitaA.YokoyamaT.NonobeY.HasabaY.SasakiT.. . . TakemoriH. (2014). Altered actions of memantine and NMDA-induced currents in a new Grid2-deleted mouse line. Genes, 5(4), 1095–1114. https://doi.org/10.3390/genes5041095
37.
Lasky-SuJ.NealeB. M.FrankeB.AnneyR. J.ZhouK.MallerJ. B.. . . FaraoneS. V. (2008). Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. American Journal of Medical Genetics: Part B Neuropsychiatric Genetics, 147B(8), 1345–1354. https://doi.org/10.1002/ajmg.b.30867
38.
LehohlaM.KellawayL.RussellV. A. (2004). NMDA receptor function in the prefrontal cortex of a rat model for attention-deficit hyperactivity disorder. Metabolic Brain Disease, 19(1–2), 35–42.
39.
MackieS.ShawP.LenrootR.PiersonR.GreensteinD. K.NugentT. F.III. . . RapoportJ. L. (2007). Cerebellar development and clinical outcome in attention deficit hyperactivity disorder. American Journal of Psychiatry, 164(4), 647–655. https://doi.org/10.1176/ajp.2007.164.4.647
40.
MasiG.ManfrediA.NieriG.MuratoriP.PfannerC.MiloneA. (2017). A naturalistic comparison of methylphenidate and risperidone monotherapy in drug-naive youth with attention-deficit/hyperactivity disorder comorbid with oppositional defiant disorder and aggression. Journal of Clinical Psychopharmacology, 37(5), 590–594. https://doi.org/10.1097/jcp.0000000000000747
41.
MedinT.JensenV.SkareO.Storm-MathisenJ.HvalbyO.BergersenL. H. (2019). Altered alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function and expression in hippocampus in a rat model of attention-deficit/hyperactivity disorder (ADHD). Behavioural Brain Research, 360, 209–215. https://doi.org/10.1016/j.bbr.2018.12.028
42.
MichielsenM.SemeijnE.ComijsH. C.van de VenP.BeekmanA. T.DeegD. J.KooijJ. J. (2012). Prevalence of attention-deficit hyperactivity disorder in older adults in the Netherlands. British Journal of Psychiatry, 201(4), 298–305. https://doi.org/10.1192/bjp.bp.111.101196
43.
Moreno-GarciaI.Delgado-PardoG.Roldan-BlascoC. (2015). Attention and response control in ADHD. Evaluation through integrated visual and auditory continuous performance test. Spanish Journal of Psychology, 18, E1. https://doi.org/10.1017/sjp.2015.2
44.
NaaijenJ.BraltenJ.PoelmansG.GlennonJ. C.FrankeB.BuitelaarJ. K. (2017). Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: Association to overlapping traits in ADHD and autism. Translational Psychiatry, 7(1), e999. https://doi.org/10.1038/tp.2016.273
45.
NaumovaD.GrizenkoN.SenguptaS. M.JooberR. (2019). DRD4 exon 3 genotype and ADHD: Randomised pharmacodynamic investigation of treatment response to methylphenidate. World Journal of Biological Psychiatry, 20, 486–495. https://doi.org/10.1080/15622975.2017.1410221
46.
PintoD.DelabyE.MericoD.BarbosaM.MerikangasA.KleiL.. . . SchererS. W. (2014). Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. American Journal of Human Genetics, 94(5), 677–694. https://doi.org/10.1016/j.ajhg.2014.03.018
47.
PolanczykG. V.SalumG. A.SugayaL. S.CayeA.RohdeL. A. (2015). Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. Journal of Child Psychology and Psychiatry, 56(3), 345–365. https://doi.org/10.1111/jcpp.12381
48.
RommelseN. N.FrankeB.GeurtsH. M.HartmanC. A.BuitelaarJ. K. (2010). Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder. European Child & Adolescent Psychiatry, 19(3), 281–295. https://doi.org/10.1007/s00787-010-0092-x
49.
StergiakouliE.HamshereM.HolmansP.LangleyK.ZaharievaI.HawiZ.. . . ThaparA. (2012). Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD. American Journal of Psychiatry, 169(2), 186–194. https://doi.org/10.1176/appi.ajp.2011.11040551
50.
StevensM. C.Haney-CaronE. (2012). Comparison of brain volume abnormalities between ADHD and conduct disorder in adolescence. Journal of Psychiatry & Neuroscience, 37(6), 389–398. https://doi.org/10.1503/jpn.110148
51.
StevensonJ. M.ReillyJ. L.HarrisM. S.PatelS. R.WeidenP. J.PrasadK. M.. . . BishopJ. R. (2016). Antipsychotic pharmacogenomics in first episode psychosis: A role for glutamate genes. Translational Psychiatry, 6, e739. https://doi.org/10.1038/tp.2016.10
SurmanC. B.HammernessP. G.PettyC.SpencerT.DoyleR.NapoleanS.. . . BiedermanJ. (2013). A pilot open label prospective study of memantine monotherapy in adults with ADHD. World Journal of Biological Psychiatry, 14(4), 291–298. https://doi.org/10.3109/15622975.2011.623716
55.
TaghdiriM.KashefA.AbbassiG.MoshtaghA.SadatianN.FardaeiM.. . . KariminejadR. (2019). Further delineation of the phenotype caused by a novel large homozygous deletion of GRID2 gene in an adult patient. Clinical Case Reports, 7(6), 1149–1153. https://doi.org/10.1002/ccr3.2020
ThompsonJ. A.ZimanM. (2011). Pax genes during neural development and their potential role in neuroregeneration. Progress in Neurobiology, 95(3), 334–351. https://doi.org/10.1016/j.pneurobio.2011.08.012
58.
TuricD.LangleyK.MillsS.StephensM.LawsonD.GovanC.. . . ThaparA. (2004). Follow-up of genetic linkage findings on chromosome 16p13: Evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD. Molecular Psychiatry, 9(2), 169–173. https://doi.org/10.1038/sj.mp.4001387
59.
TyeS. J.MillerA. D.BlahaC. D. (2013). Ventral tegmental ionotropic glutamate receptor stimulation of nucleus accumbens tonic dopamine efflux blunts hindbrain-evoked phasic neurotransmission: Implications for dopamine dysregulation disorders. Neuroscience, 252, 337–345. https://doi.org/10.1016/j.neuroscience.2013.08.010
60.
UtineG. E.HalilogluG.SalanciB.CetinkayaA.KiperP. O.AlanayY.. . . AlikasifogluM. (2013). A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy. Journal of child neurology, 28(7), 926–932. https://doi.org/10.1177/0883073813484967
61.
VloetT. D.GilsbachS.NeufangS.FinkG. R.Herpertz-DahlmannB.KonradK. (2010). Neural mecha-nisms of interference control and time discrimination in attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 49(4), 356–367.
62.
VolkowN. D.SwansonJ. M. (2013). Clinical practice: Adult attention deficit-hyperactivity disorder. New England Journal of Medicine, 369(20), 1935–1944. https://doi.org/10.1056/NEJMcp1212625
63.
WangT.LiuK.LiZ.XuY.LiuY.ShiW.ChenL. (2017). Prevalence of attention deficit/hyperactivity disorder among children and adolescents in China: A systematic review and meta-analysis. BMC Psychiatry, 17(1), Article 32. https://doi.org/10.1186/s12888-016-1187-9
64.
WardL. D.KellisM. (2012). HaploReg: A resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Research, 40, D930–D934. https://doi.org/10.1093/nar/gkr917
65.
YamasakiM.MiyazakiT.AzechiH.AbeM.NatsumeR.HagiwaraT.. . . WatanabeM. (2011). Glutamate receptor delta2 is essential for input pathway-dependent regulation of synaptic AMPAR contents in cerebellar Purkinje cells. Journal of Neuroscience, 31(9), 3362–3374. https://doi.org/10.1523/jneurosci.5601-10.2011
66.
YuenE. Y.ZhongP.LiX.WeiJ.YanZ. (2013). Restoration of glutamatergic transmission by dopamine D4 receptors in stressed animals. Journal of Biological Chemistry, 288(36), 26112–26120. https://doi.org/10.1074/jbc.M112.396648
67.
YuenE. Y.ZhongP.YanZ. (2010). Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors. Proceedings of the National Academy of Sciences of the United States of America, 107(51), 22308–22313. https://doi.org/10.1073/pnas.1010025108
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