Sex-dependent Complex Association of TPH2 with Multiple Dimensions of ADHD

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.