title: Norepinephrine genes predict response time variability and methylphenidate-induced changes in neuropsychological function in attention deficit hyperactivity disorder.
abstract: Noradrenergic dysfunction may be associated with cognitive impairments in attention-deficit/hyperactivity disorder (ADHD), including increased response time variability, which has been proposed as a leading endophenotype for ADHD. The aim of this study was to examine the relationship between polymorphisms in the α-2A-adrenergic receptor (ADRA2A) and norepinephrine transporter (SLC6A2) genes and attentional performance in ADHD children before and after pharmacological treatment.One hundred one medication-naive ADHD children were included. All subjects were administered methylphenidate (MPH)-OROS for 12 weeks. The subjects underwent a computerized comprehensive attention test to measure the response time variability at baseline before MPH treatment and after 12 weeks. Additive regression analyses controlling for ADHD symptom severity, age, sex, IQ, and final dose of MPH examined the association between response time variability on the comprehensive attention test measures and allelic variations in single-nucleotide polymorphisms of the ADRA2A and SLC6A2 before and after MPH treatment.Increasing possession of an A allele at the G1287A polymorphism of SLC6A2 was significantly related to heightened response time variability at baseline in the sustained (P = 2.0 × 10) and auditory selective attention (P = 1.0 × 10) tasks. Response time variability at baseline increased additively with possession of the T allele at the DraI polymorphism of the ADRA2A gene in the auditory selective attention task (P = 2.0 × 10). After medication, increasing possession of a G allele at the MspI polymorphism of the ADRA2A gene was associated with increased MPH-related change in response time variability in the flanker task (P = 1.0 × 10).Our study suggested an association between norepinephrine gene variants and response time variability measured at baseline and after MPH treatment in children with ADHD. Our results add to a growing body of evidence, suggesting that response time variability is a viable endophenotype for ADHD and suggesting its utility as a surrogate end point for measuring stimulant response in pharmacogenetic studies.
authors.affiliation: Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Bung-Nyun
authors.initials: BN
authors.lastname: Kim
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Tarrant D R
authors.initials: TD
authors.lastname: Cummins
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bellgrove
authors.forename: Ziarih
authors.initials: Z
authors.lastname: Hawi
authors.forename: Soon-Beom
authors.initials: SB
authors.lastname: Hong
authors.forename: Young-Hui
authors.initials: YH
authors.lastname: Yang
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Min-Sup
authors.initials: MS
authors.lastname: Shin
authors.forename: Soo-Churl
authors.initials: SC
authors.lastname: Cho
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Son
authors.forename: Yun-Mi
authors.initials: YM
authors.lastname: Shin
authors.forename: Un-Sun
authors.initials: US
authors.lastname: Chung
authors.forename: Doug-Hyun
authors.initials: DH
authors.lastname: Han
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D002648:Child; D003936:Diagnosis, Computer-Assisted; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D012044:Regression Analysis; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C547768:ADRA2A protein, human; D000697:Central Nervous System Stimulants; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018341:Receptors, Adrenergic, alpha-2; C493227:SLC6A2 protein, human; D008774:Methylphenidate; D009638:Norepinephrine