Restricted accessResearch articleFirst published online 2021-7
Monoaminergic Genetic Variants,Prefrontal Cortex–Amygdala Circuit,and Emotional Symptoms in Children With ADHD: Exploration Based on the Gene–Brain–Behavior Relationship
Objective: This study aimed to explore the association between monoaminergic genetic variants and emotional lability (EL) symptoms in children with ADHD. In addition, genetic effects on prefrontal cortex (PFC)–amygdala functional connectivity (FC) were investigated. Method: Children with ADHD and controls were genotyped for five monoaminergic genetic variants and were evaluated for EL symptoms. Imaging genetic exploration was conducted with previously reported aberrant PFC–amygdala resting-state functional connectivities (RSFCs) as target features. Results: A genotypic effect on EL symptoms was only found for NET1-rs3785143, indicating higher EL symptoms in TT genotype carriers than in C-allele carriers. Imaging genetic analyses indicated a marginal effect of NET1-rs3785143 on ADHD-altered FC between the superficial amygdala (SFA) and middle frontal gyrus (MFG). Mediation analysis suggested potential effects of NET1-rs3785143 via RSFC (SFA–MFG) on EL. Conclusion:NET1 variants might participate in the pathogenesis of EL in children with ADHD by influencing the function of the PFC–amygdala circuit.
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.).
2.
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). American Psychiatric Publishing.
3.
ArnstenA. F. (2009). The emerging neurobiology of attention deficit hyperactivity disorder: The key role of the prefrontal association cortex. Journal of Pediatrics, 154, I–S43.
4.
ArnstenA. F. (2011). Catecholamine influences on dorsolateral prefrontal cortical networks. Biological Psychiatry, 69, e89–e99.
5.
ArnstenA. F.PliszkaS. R. (2011). Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders. Pharmacology Biochemistry and Behavior, 99, 211–216.
6.
ArnstenA. F.WangM. (2016). Targeting prefrontal cortical systems for drug development: Potential therapies for cognitive disorders. Annual Review of Pharmacology and Toxicology, 56, 339–360.
7.
BarkleyR. A. (2010). Deficient emotional self-regulation: A core component of attention-deficit/hyperactivity disorder. Journal of ADHD & Related Disorders, 1, 5–37.
8.
BiedermanJ.ChanJ.FaraoneS. V.WoodworthK. Y.SpencerT. J.WozniakJ. R. (2018). A Familial risk analysis of emotional dysregulation: A controlled study. Journal of Attention Disorders, 22, 848–854.
9.
BrookesK.XuX.ChenW.ZhouK.NealeB.LoweN.. . . AshersonP. (2006). The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: Association signals in DRD4, DAT1 and 16 other genes. Molecular Psychiatry, 11, 934–953.
10.
ChangC. C.ChangH. A.FangW. H.ChangT. C.HuangS. Y. (2017). Gender-specific association between serotonin transporter polymorphisms (5-HTTLPR and rs25531) and neuroticism, anxiety and depression in well-defined healthy Han Chinese. Journal of Affective Disorders, 207, 422–428.
11.
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, 63–75.
12.
DingY. S.NaganawaM.GallezotJ. D.NabulsiN.LinS. F.RopchanJ.. . . LaruelleM. (2014). Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD. Neuroimage, 86, 164–171.
13.
EdenA. S.SchreiberJ.AnwanderA.KeuperK.LaegerI.ZwanzgerP.. . . DobelC. (2015). Emotion regulation and trait anxiety are predicted by the microstructure of fibers between amygdala and prefrontal cortex. Journal of Neuroscience, 35, 6020–6027.
14.
ElliottL. T.SharpK.Alfaro-AlmagroF.ShiS.MillerK. L.DouaudG.. . . SmithS. M. (2018). Genome-wide association studies of brain imaging phenotypes in UK Biobank. Nature, 562, 210–216.
15.
FaraoneS. V.RostainA. L.BladerJ.BuschB.ChildressA. C.ConnorD. F.NewcornJ. H. (2018). Practitioner review: Emotional dysregulation in attention-deficit/hyperactivity disorder—Implications for clinical recognition and intervention. Journal of Child Psychology and Psychiatry. https://doi.org/10.1111/jcpp.12899
16.
FowlerT.LangleyK.RiceF.van den BreeM. B.RossK.WilkinsonL. S.. . . ThaparA. (2009). Psychopathy trait scores in adolescents with childhood ADHD: The contribution of genotypes affecting MAOA, 5HTT and COMT activity. Psychiatric Genetics, 19, 312–319.
17.
GrossJ. J. (2007). The handbook of emotion regulation. Guilford Press.
18.
HaririA. R.DrabantE. M.WeinbergerD. R. (2006). Imaging genetics: Perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing. Biological Psychiatry, 59, 888–897.
19.
HayesA. F. (2012). PROCESS: A versatile computational tool for observed variable mediation, moderation, and conditional process modeling [White paper]. http://www.afhayes.com/public/process2012.pdf
20.
HulvershornL. A.MennesM.CastellanosF. X.Di MartinoA.MilhamM. P.HummerT. A.RoyA. K. (2014). Abnormal amygdala functional connectivity associated with emotional lability in children with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 53, 351–361.
21.
JiN.ShuaiL.ChenY.LiuL.LiH. M.LiZ. H.. . . WangY. F. (2011). Dopamine beta-hydroxylase gene associates with Stroop color-word task performance in Han Chinese children with attention deficit/hyperactivity disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 156B, 730–736.
22.
JinJ.LiuL.GaoQ.ChanR. C.LiH.ChenY.. . . QianQ. (2016). The divergent impact of COMT Val158Met on executive function in children with and without attention-deficit/hyperactivity disorder. Genes Brain and Behavior, 15, 271–279.
23.
KimJ. W.BiedermanJ.McGrathC. L.DoyleA. E.MickE.FagernessJ.. . . FaraoneS. V. (2008). Further evidence of association between two NET single-nucleotide polymorphisms with ADHD. Molecular Psychiatry, 13, 624–630.
24.
LiJ.WangY.ZhouR.ZhangH.YangL.WangB.FaraoneS. V. (2007). Association between polymorphisms in serotonin transporter gene and attention deficit hyperactivity disorder in Chinese Han subjects. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 144B, 14–19.
25.
LiuL.ChenW.SunL.ChengJ.SuY.RudaizkyD.. . . WangY. F. (2020). The characteristics and age effects of emotional lability in ADHD children with and without oppositional defiant disorder. Journal of Attention Disorders, 24(14), 2042–2053. https://doi.org/10.1177/1087054717745594
26.
LiuL.ChenW.VitoratouS.SunL.YuX.Hagger-JohnsonG.. . . WangY. (2016). Is emotional lability distinct from “angry/irritable mood,” “negative affect,” or other subdimensions of oppositional defiant disorder in children with ADHD?Journal of Attention Disorders, 23(8), 859–868.
27.
LiuL.ChengJ.LiH.YangL.QianQ.WangY. (2015a). The possible involvement of genetic variants of NET1 in the etiology of attention-deficit/hyperactivity disorder comorbid with oppositional defiant disorder. Journal of Child Psychology and Psychiatry, 56, 58–66.
28.
LiuL.GaoQ.LiH.WangY.YangL.SunL.. . . WangY. (2015b). Influence of ODD diagnosis on the association between NET1 and attention-deficit/hyperactivity disorder. Zhonghua Yi Xue Za Zhi, 95, 3351–3356.
29.
LiuL.GuanL. L.ChenY.JiN.LiH. M.LiZ. H.. . . WangY. F. (2011). Association analyses of MAOA in Chinese Han subjects with attention-deficit/hyperactivity disorder: Family-based association test, case-control study, and quantitative traits of impulsivity. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 156B, 737–748.
30.
LivakK. J. (1999). Allelic discrimination using fluorogenic probes and the 5’ nuclease assay. Genetic Analysis, 14, 143–149.
31.
MerwoodA.ChenW.RijsdijkF.SkirrowC.LarssonH.ThaparA.. . . AshersonP. (2014). Genetic associations between the symptoms of attention-deficit/hyperactivity disorder and emotional lability in child and adolescent twins. Journal of the American Academy of Child and Adolescent Psychiatry, 53, 209–220.
32.
OchsnerK. N.GrossJ. J. (2005). The cognitive control of emotion. Trends in Cognitive Sciences, 9, 242–249.
33.
PetrovicP.CastellanosF. X. (2016). Top-down dysregulation—From ADHD to emotional instability. Frontiers in Behavioral Neuroscience, 10, Article 70.
34.
PosnerJ.NagelB. J.MaiaT. V.MechlingA.OhM.WangZ.PetersonB. S. (2011). Abnormal amygdalar activation and connectivity in adolescents with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 50, 828–837.
35.
RubiaK.AlegriaA. A.BrinsonH. (2014). Brain abnormalities in attention-deficit hyperactivity disorder: A review. Revue Neurologique, 58(Suppl. 1), S3–S16.
36.
SeymourK. E.MacateeR.Chronis-TuscanoA. (2016). Frustration tolerance in youth with ADHD. Journal of Attention Disorders, 23(11), 1229–1239.
37.
ShawP.StringarisA.NiggJ.LeibenluftE. (2014). Emotion dysregulation in attention deficit hyperactivity disorder. American Journal of Psychiatry, 171, 276–293.
38.
SobanskiE.BanaschewskiT.AshersonP.BuitelaarJ.ChenW.FrankeB.. . . FaraoneS. V. (2010). Emotional lability in children and adolescents with attention deficit/hyperactivity disorder (ADHD): Clinical correlates and familial prevalence. Journal of Child Psychology and Psychiatry, 51, 915–923.
39.
SongX. W.DongZ. Y.LongX. Y.LiS. F.ZuoX. N.ZhuC. Z.. . . ZangY. F. (2011). REST: A toolkit for resting-state functional magnetic resonance imaging data processing. PLOS ONE, 6, Article e25031.
40.
StahlS. M. (2003). Neurotransmission of cognition, part 3. Mechanism of action of selective NRIs: Both dopamine and norepinephrine increase in prefrontal cortex. Journal of Clinical Psychiatry, 64, 230–231.
41.
WonE.HamB. J. (2016). Imaging genetics studies on monoaminergic genes in major depressive disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 64, 311–319.
42.
WuZ.YangL.WangY. (2014). Applying imaging genetics to ADHD: The promises and the challenges. Molecular Neurobiology, 50, 449–462.
43.
XuT. Y. (1999). Rating scales for mental health. Chinese Mental Health Journal.
44.
XuX.HawiZ.BrookesK. J.AnneyR.BellgroveM.FrankeB.. . . AshersonP. (2008). Replication of a rare protective allele in the noradrenaline transporter gene and ADHD. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B, 1564–1567.
45.
YuX.LiuL.ChenW.CaoQ.ZepfF. D.JiG.. . . WangY. (2020). Integrity of amygdala subregion-based functional networks and emotional lability in drug-naive boys with ADHD. Journal of Attention Disorders, 24(12), 1661–1673. https://doi.org/10.1177/1087054716661419
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