KCNJ6 variants modulate reward-related brain processes and impact executive functions in attention-deficit/hyperactivity disorder.
5' Untranslated Regions
Adult
Attention Deficit Disorder with Hyperactivity
/ genetics
Brain
/ physiopathology
Brain Mapping
Case-Control Studies
Dopamine
/ metabolism
Electroencephalography
Executive Function
/ physiology
Family Health
Female
G Protein-Coupled Inwardly-Rectifying Potassium Channels
/ genetics
Haplotypes
Humans
Magnetic Resonance Imaging
Male
Mutagenesis
Phenotype
Polymorphism, Single Nucleotide
Reward
Young Adult
ADHD
KCNJ6
dopamine
executive functions
reward
Journal
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
ISSN: 1552-485X
Titre abrégé: Am J Med Genet B Neuropsychiatr Genet
Pays: United States
ID NLM: 101235742
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
25
11
2018
revised:
04
04
2019
accepted:
06
05
2019
pubmed:
18
5
2019
medline:
17
2
2021
entrez:
18
5
2019
Statut:
ppublish
Résumé
KCNJ6, encoding a potassium channel subunit, regulates the excitability of dopaminergic neurons and is expressed in attention-deficit/hyperactivity disorder (ADHD)-relevant brain regions. As a potential ADHD risk gene, KCNJ6, therefore, may contribute to the endophenotypic variation of the disorder. The impact of two SNPs, rs7275707 and rs6517442, both located in the transcriptional control region of KCNJ6, on reporter gene expression was explored in cultured cells. The KCNJ6 variants were then tested for association with ADHD and personality traits in a family-based sample (165 affected children) and an adult case-control sample (450 patients, 426 controls). Furthermore, the genotypic influence on performance in an n-back task and a cued continuous performance test (cCPT) was investigated by electroencephalography recordings. Finally, rs6517442 function was assessed by a reward anticipation paradigm using functional magnetic resonance imaging. Different haplotypes of rs7275707 and rs6517442 significantly influenced KCNJ6 gene expression proving their functional relevance on the molecular level. In the family-based children sample rs7275707 was associated with ADHD (p = .038). Moreover, rs7275707 showed association with the personality trait of Reward Dependence (p = .031). In the ADHD group, both rs7275707 and rs6517442 influenced the Go-centroid location in the cCPT and the N200 amplitude in the n-back task. Furthermore, ventral striatal activation was impacted by rs6517442 during reward anticipation. Our data indicate that functional variants of KCNJ6 influence brain activity during reward-related and executive processes supporting the view of a differential, age-dependent modulatory impact of dopamine-related brain processes in ADHD risk.
Identifiants
pubmed: 31099984
doi: 10.1002/ajmg.b.32734
doi:
Substances chimiques
5' Untranslated Regions
0
G Protein-Coupled Inwardly-Rectifying Potassium Channels
0
KCNJ6 protein, human
0
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
247-257Informations de copyright
© 2019 Wiley Periodicals, Inc.
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