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KCNJ6 variants modulate reward-related brain processes and impact executive functions in attention-deficit/hyperactivity disorder.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics ( IF 1.6 ) Pub Date : 2019-05-17 , DOI: 10.1002/ajmg.b.32734
Georg C Ziegler 1 , Christoph Röser 1 , Tobias Renner 2 , Tim Hahn 3 , Ann-Christine Ehlis 4 , Heike Weber 1 , Astrid Dempfle 5 , Susanne Walitza 6 , Christian Jacob 1, 7 , Marcel Romanos 8 , Andreas J Fallgatter 4 , Andreas Reif 1, 9 , Klaus-Peter Lesch 1, 10, 11
Affiliation  

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.

中文翻译:

KCNJ6变体调节与奖赏相关的大脑过程,并影响注意力不足/多动症的执行功能。

编码钾通道亚基的KCNJ6调节多巴胺能神经元的兴奋性,并在与注意力缺陷/多动症(ADHD)相关的大脑区域表达。因此,作为潜在的多动症危险基因,KCNJ6可能导致该疾病的内表型变异。在培养的细胞中探索了两个均位于KCNJ6转录控制区的rs7275707和rs6517442 SNP对报告基因表达的影响。该KCNJ6变体,然后用一个基于家庭的样本多动症和人格特质(165名受影响的儿童)和成人病例对照样本(450例,426个控件)的关联进行测试。此外,基因型对n中表现的影响通过脑电图记录调查了后备任务和提示的连续性能测试(cCPT)。最后,使用功能磁共振成像通过奖励预期范式评估rs6517442的功能。rs7275707和rs6517442的不同单倍型显着影响了KCNJ6基因的表达,证明了它们在分子水平上的功能相关性。在家庭儿童中,样本rs7275707与ADHD相关(p = .038)。此外,rs7275707与奖励依赖的人格特质相关p = .031)。在多动症组中,rs7275707和rs6517442都影响cCPT中的Go质心位置和n中的N200幅度。后退任务。此外,在奖励预期期间,rs6517442影响了腹侧纹状体的激活。我们的数据表明,KCNJ6的功能性变异会在与奖励相关的执行过程中影响大脑活动,这支持了多巴胺相关的大脑过程在多动症风险中的差异,与年龄有关的调节作用的观点。
更新日期:2019-05-17
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