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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). 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. 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. These results suggest that there may be a complex association of TPH2 in the etiology of ADHD, with a sex-specific effect. • Family-based association tests show specific findings with TPH2 and girls with ADHD. • Sex-specific effect is observed with behaviour and cognitive dimensions. • Differential association also observed with treatment response in girls. • Appears that there may be different etiological pathways in girls with ADHD. • Results may inform sex-specific pharmacological interventions. [ABSTRACT FROM AUTHOR]

Objective: To compare the pattern of familial aggregation of psychopathology in children who are good responders (GR) to methylphenidate (MPH) versus those who are poor responders (PR).Method: A total of 118 clinically referred children ages 6 to 12 years, diagnosed with ADHD participated in a double-blind, placebo-controlled, randomized 2-week crossover trial of MPH from 1999 to 2004. A low dose of 0.5 mg/kg of body weight of MPH divided in two equal doses was used. Family history was obtained by interviewing at least one key historian relative of each subject using Family Interview for Genetic Studies. Information was collected on 342 first-degree and 1,151 second-degree relatives of children with attention-deficit/hyperactivity disorder.Results: Forty-four subjects showed mild or no improvement (PR) and 74 showed moderate or very much improvement (GR) on MPH over placebo. First-degree relatives of GR subjects were at significantly higher risk of attention-deficit/hyperactivity disorder than the relatives of PR subjects (p<.05). Second-degree relatives of the GR were at significantly higher risk of antisocial personality disorder compared to the relatives of PR subjects (p<.05).Conclusions: The significantly higher presence of attention-deficit/hyperactivity disorder in the first-degree relatives and of antisocial personality disorder in the second-degree relatives of GR children suggests that this group may, at least partially, be distinct from the PR group on the basis of genetic determinants. [ABSTRACT FROM AUTHOR]