TY - JOUR
T1 - KCNJ6 variants modulate reward-related brain processes and impact executive functions in attention-deficit/hyperactivity disorder
AU - Ziegler, Georg C.
AU - Roeser, Christoph
AU - Renner, Tobias
AU - Hahn, Tim
AU - Ehlis, Ann-Christine
AU - Weber, Heike
AU - Dempfle, Astrid
AU - Walitza, Susanne
AU - Jacob, Christian
AU - Romanos, Marcel
AU - Fallgatter, Andreas J.
AU - Reif, Andreas
AU - Lesch, Klaus-Peter
N1 - Funding Information:
We are grateful to all patients for their participation in the study. This study was supported by the Deutsche Forschungsgemeinschaft (DFG: CRU 125, CRC TRR 58 A1/A5, CRC1193 Z03), the European Union's Seventh Framework Programme under Grant No. 602805 (Aggressotype), the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNICE), 667302 (CoCA) and 643051 (MiND), Fritz Thyssen Stiftung (No. 10.13.1185), ERA-Net NEURON/RESPOND, No. 01EW1602B, and 5-100 Russian Academic Excellence Project. In addition, this work was supported by the European College of Neuropsychopharmacology (ECNP Network “ADHD across the lifespan”).
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - ADHD
KW - dopamine
KW - executive functions
KW - KCNJ6
KW - reward
KW - RECTIFYING K+ CHANNELS
KW - SUBSTANTIA-NIGRA
KW - DOPAMINERGIC-NEURONS
KW - THETA OSCILLATIONS
KW - VENTRAL STRIATUM
KW - RESPONSE CONTROL
KW - GENE
KW - ANTICIPATION
KW - ASSOCIATION
KW - HYPERACTIVITY
U2 - 10.1002/ajmg.b.32734
DO - 10.1002/ajmg.b.32734
M3 - Article
C2 - 31099984
SN - 1552-4841
VL - 183
SP - 247
EP - 257
JO - American Journal of Medical Genetics Part B-neuropsychiatric Genetics
JF - American Journal of Medical Genetics Part B-neuropsychiatric Genetics
IS - 5
ER -