Background

Tryptophan hydroxylase 2 (TPH2) is a key enzyme in the biosynthesis of serotonin in the brain. This study aims to investigate the role of a functional variant in TPH2 (rs17110747) in the pathophysiology of ADHD. This variant has been implicated in mood disorders in recent meta-analysis. This study uses a comprehensive approach that combines association testing and pharmaco-dynamic evaluation of behaviour, in a large sample of children with ADHD (n = 570).

Methods

The association between various ADHD relevant traits and rs17110747 was analyzed using family-based association tests (FBAT). Children were assessed by parents, teachers and research staff under three experimental conditions (EC): baseline, placebo, and methylphenidate using a double-blind placebo-controlled crossover trial.

Outcomes

FBAT analysis conducted in a sample stratified based on sex of the proband, showed that there was a highly significant overtransmission of the G allele from parents to affected girls. In addition, significant association with several behavioral and cognitive dimensions of ADHD was observed only when the proband was female. Further, girls with the G/G genotype (rs17110747) had greater response to placebo when evaluated by parents.

Interpretation

These results suggest that there may be a complex association of TPH2 in the etiology of ADHD, with a sex-specific effect.

中文翻译：

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TPH2与多动症多维度的性别依赖性复杂关联

背景

色氨酸羟化酶 2 (TPH2) 是大脑中血清素生物合成的关键酶。本研究旨在探讨TPH2 (rs17110747) 中的功能变异在 ADHD 病理生理学中的作用。在最近的荟萃分析中，这种变体与情绪障碍有关。本研究使用了一种综合方法，将关联测试和行为药效学评估相结合，对大量 ADHD 儿童样本 ( n  = 570)。

方法

使用基于家庭的关联测试 (FBAT) 分析了各种 ADHD 相关性状与 rs17110747 之间的关联。家长、教师和研究人员使用双盲安慰剂对照交叉试验在三种实验条件 (EC) 下对儿童进行评估：基线、安慰剂和哌醋甲酯。

结果

在基于先证者性别分层的样本中进行的 FBAT 分析表明，G等位基因从父母到受影响的女孩存在高度显着的过度传递。此外，仅当先证者为女性时，才观察到与 ADHD 的几个行为和认知维度的显着关联。此外，当父母评估时，具有G/G基因型 (rs17110747) 的女孩对安慰剂的反应更大。

解释

这些结果表明TPH2在 ADHD 的病因学中可能存在复杂的关联，具有性别特异性效应。