Association between COMT methylation and response to treatment in children with ADHD.
Attention-deficit/hyperactivity disorder (ADHD)
COMT
Conners'
Methylation
Pharmacoepigenetics
Treatment response
Journal
Journal of psychiatric research
ISSN: 1879-1379
Titre abrégé: J Psychiatr Res
Pays: England
ID NLM: 0376331
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
11
05
2020
revised:
24
12
2020
accepted:
04
01
2021
pubmed:
17
1
2021
medline:
15
5
2021
entrez:
16
1
2021
Statut:
ppublish
Résumé
COMT had been considered a promising candidate gene in pharmacogenetic studies in ADHD; yet the findings from these studies have been inconsistent. Part of these inconsistencies could be related to epigenetic mechanisms (including DNA methylation). Here we investigated the role of genetic variants of the COMT gene on the methylation levels of CpG sites in the same gene and explored the effect of methylation on methylphenidate (MPH) and placebo (PBO) response in children with ADHD. Two hundred and thirty children with ADHD (6-12 years) participated in a randomized, double-blind, placebo-controlled crossover trial with MPH. Univariate analysis was performed to examine the associations between genotypes in the COMT gene and DNA methylation in the same genetic loci. Association between the DNA methylation of 11 CpG sites and PBO/MPH responses were then assessed using spearman's correlation analysis in 212 children. Multiple linear regression analyses were performed to test the interaction between these factors while accounting for sex. Associations were observed between specific genetic variants and methylation level of cg20709110. Homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), Val/Val (rs4680) and the haplotype (ACCVal/GCGVal) were significantly associated with higher level of methylation. This CpG showed a significant correlation with placebo response (r = -0.15, P = 0.045) according to the teachers' evaluation, and a close-to significance correlation with response to MPH according to parents' evaluation (r = -0.134, p = 0.051). Regression analysis showed that in the model including rs4818, sex and DNA methylation of cg20709110 contributed significantly to treatment response. These preliminary results could provide evidence for the effect of genetic variations on methylation level and the involvement of the epigenetic variation of COMT loci in modulating the response to treatment in ADHD. clinicaltrials.gov, number NCT00483106.
Sections du résumé
BACKGROUND
COMT had been considered a promising candidate gene in pharmacogenetic studies in ADHD; yet the findings from these studies have been inconsistent. Part of these inconsistencies could be related to epigenetic mechanisms (including DNA methylation). Here we investigated the role of genetic variants of the COMT gene on the methylation levels of CpG sites in the same gene and explored the effect of methylation on methylphenidate (MPH) and placebo (PBO) response in children with ADHD.
METHODS
Two hundred and thirty children with ADHD (6-12 years) participated in a randomized, double-blind, placebo-controlled crossover trial with MPH. Univariate analysis was performed to examine the associations between genotypes in the COMT gene and DNA methylation in the same genetic loci. Association between the DNA methylation of 11 CpG sites and PBO/MPH responses were then assessed using spearman's correlation analysis in 212 children. Multiple linear regression analyses were performed to test the interaction between these factors while accounting for sex.
RESULTS
Associations were observed between specific genetic variants and methylation level of cg20709110. Homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), Val/Val (rs4680) and the haplotype (ACCVal/GCGVal) were significantly associated with higher level of methylation. This CpG showed a significant correlation with placebo response (r = -0.15, P = 0.045) according to the teachers' evaluation, and a close-to significance correlation with response to MPH according to parents' evaluation (r = -0.134, p = 0.051). Regression analysis showed that in the model including rs4818, sex and DNA methylation of cg20709110 contributed significantly to treatment response.
CONCLUSIONS
These preliminary results could provide evidence for the effect of genetic variations on methylation level and the involvement of the epigenetic variation of COMT loci in modulating the response to treatment in ADHD.
TRIAL REGISTRATION
clinicaltrials.gov, number NCT00483106.
Identifiants
pubmed: 33453563
pii: S0022-3956(21)00009-1
doi: 10.1016/j.jpsychires.2021.01.008
pii:
doi:
Substances chimiques
Central Nervous System Stimulants
0
Methylphenidate
207ZZ9QZ49
COMT protein, human
EC 2.1.1.6
Catechol O-Methyltransferase
EC 2.1.1.6
Banques de données
ClinicalTrials.gov
['NCT00483106']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
86-93Subventions
Organisme : CIHR
ID : MOP 53309
Pays : Canada
Organisme : CIHR
ID : MOP 84537
Pays : Canada
Organisme : CIHR
ID : MOP 126023
Pays : Canada
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.