Association between COMT methylation and response to treatment in children with ADHD.

TitleAssociation between COMT methylation and response to treatment in children with ADHD.
Publication TypeJournal Article
Year of Publication2021
AuthorsFageera W, Chaumette B, Fortier M-È, Grizenko N, Labbe A, Sengupta SM, Joober R
JournalJ Psychiatr Res
Date Published2021 03
KeywordsAttention Deficit Disorder with Hyperactivity, Catechol O-Methyltransferase, Central Nervous System Stimulants, Child, Double-Blind Method, Genotype, Haplotypes, Humans, Methylation, Methylphenidate, Treatment Outcome

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:, number NCT00483106.

Alternate JournalJ Psychiatr Res
PubMed ID33453563
Grant ListMOP 53309 / / CIHR / Canada
MOP 84537 / / CIHR / Canada
MOP 126023 / / CIHR / Canada