Impact of COMT, DIRAS2, and LPHN3 on emotional processing in ADHD

注意缺陷多动障碍(ADHD)是高度可遗传的，其核心症状，包括注意力不集中、多动和冲动，也可出现在成年期，严重影响受影响个人的生活质量。对于ADHD患者来说，情绪信号的处理尤其具有挑战性：一方面，ADHD儿童和成人都表现出对声音和面部非语言情绪信号的判断受损。另一方面，这种与社会相关的信号有可能成为干扰认知任务的干扰因素。功能磁共振成像(FMRI)的最新结果显示，ADHD儿童在判断情绪面孔时，杏仁核的反应增加。然而，成人ADHD患者情绪信号知觉障碍的神经关联及其遗传来源迄今尚不清楚。对健康受试者的基因成像研究表明，儿茶酚胺-O-甲基转移酶(COMT)的val158met基因在情绪刺激处理过程中起着至关重要的作用。此外，已有研究表明，高活性COMT基因导致前额叶皮质多巴胺能活性降低与社会认知障碍和反社会行为有关。在行为水平上，ADHD的相关基因GTP结合RAS-like 2基因(DIRAS2)和LPHN3(LPHN3)对社会行为有显著的遗传影响。这个项目的目的是确定ADHD患者的内表型，这些表型与社会认知受损有关。为此，我们计划将结构和功能磁共振与分子遗传学(成像遗传学)相结合。基于遗传和神经成像危险因素对社会认知受损的成功预测可能为这一患者组的早期和个体化治疗打开一扇窗。

Attention deficit hyperactivity disorder (ADHD) is highly heritable and its core symptoms including inattention, hyperactivity, and impulsivity can also be present in adulthood severly compromising the quality of life of affected individuals. For ADHD patients, processing of emotional signals is particularly challenging: On the one hand, impaired judgments of non-verbal emotional signals in voices and faces have been shown in both children and adults with ADHD. On the other hand, such socially relevant signals have the potential to act as distractors that can interfere with cognitive tasks. Recent results using functional magnetic resonance imaging (fMRI) demonstrated increased responses in the amygdala of children with ADHD during judgment of emotional faces. The neural correlates of the disturbed perception of emotional signals in adult ADHD as well as their genetic origins, however, are unknown so far. Genetic imaging studies in healthy participants could demonstrate a crucial role for the val158met genotype of the catecholamin-O-methyl transferase (COMT) during processing of emotional stimuli. Furthermore, it has been shown that the high-activity COMT genotype leading to decreased dopaminergic activity in the prefrontal cortex is associated with impaired social cognition and antisocial behavior. At behavioral level, a significant genetic impact on social behavior has been recently described in ADHD for the ADHD-associated genes GTP-binding RAS-like 2 gene (DIRAS2) and latrophilin 3 (LPHN3). It is the aim of this project to identify endophenotypes in ADHD which are associated with impaired social cognition. To this end, we plan to combine structural and functional MRI with molecular genetics (imaging genetics). Successful prediction of impaired social cognition based on genetic and neuroimaging risk factors might open a window for an early and individualized therapy in this patient group.