Sex-dependent complex association of TPH2 with multiple dimensions of ADHD.
Attention-deficit/hyperactivity disorder (ADHD)
Conners'
Pharmaco-genetics
Serotonin
Tryptophan hydroxylase 2 (TPH2)
Journal
Progress in neuro-psychopharmacology & biological psychiatry
ISSN: 1878-4216
Titre abrégé: Prog Neuropsychopharmacol Biol Psychiatry
Pays: England
ID NLM: 8211617
Informations de publication
Date de publication:
30 08 2021
30 08 2021
Historique:
received:
24
06
2020
revised:
18
02
2021
accepted:
23
02
2021
pubmed:
8
3
2021
medline:
8
2
2022
entrez:
7
3
2021
Statut:
ppublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 33677046
pii: S0278-5846(21)00055-5
doi: 10.1016/j.pnpbp.2021.110296
pii:
doi:
Substances chimiques
TPH2 protein, human
EC 1.14.16.4
Tryptophan Hydroxylase
EC 1.14.16.4
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
110296Informations de copyright
Copyright © 2021. Published by Elsevier Inc.