PMID- 37104367
OWN - NLM
STAT- MEDLINE
DCOM- 20230501
LR  - 20230511
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 18
IP  - 4
DP  - 2023
TI  - Serotonergic modulation of normal and abnormal brain dynamics: The genetic 
      influence of the TPH2 G-703T genotype and DNA methylation on wavelet variance in 
      children and adolescents with and without ADHD.
PG  - e0282813
LID - 10.1371/journal.pone.0282813 [doi]
LID - e0282813
AB  - Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder 
      that often persists into adulthood. Core symptoms of ADHD, such as impulsivity, 
      are caused by an interaction of genetic and environmental factors. Epigenetic 
      modifications of DNA, such as DNA methylation, are thought to mediate the 
      interplay of these factors. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting 
      enzyme in brain serotonin synthesis. The TPH2 gene has frequently been 
      investigated in relation to ADHD, e.g., showing that TPH2 G-703T (rs4570625) 
      polymorphism influences response control and prefrontal signaling in ADHD 
      patients. In this (epi)genetic imaging study we examined 144 children and 
      adolescents (74 patients, 14 females) using fMRI at rest and during performing a 
      waiting impulsivity (WI) paradigm. Both, TPH2 G-703T (rs4570625) genotype and DNA 
      methylation in the 5' untranslated region (5'UTR) of TPH2 were associated with 
      wavelet variance in fronto-parietal regions and behavioral performance, taking 
      TPH2 genotype into account. In detail, comparisons between genotypes of patients 
      and controls revealed highest wavelet variance and longest reaction times in 
      patients carrying the T allele [indicative for a gene-dosage effect, i.e., the WI 
      phenotype is a direct result of the cumulative effect of ADHD and TPH2 
      variation]. Regressions revealed a significant effect on one specific DNA 
      methylation site in ADHD patients but not controls, in terms of a significant 
      prediction of wavelet variance in fronto-parietal regions as well as premature 
      responses. By the example of the TPH2 G-703T (rs4570625) polymorphism, we provide 
      insight into how interactive genetic and DNA methylation affect the ADHD and/or 
      impulsive endophenotype.
CI  - Copyright: (c) 2023 Akhrif et al. This is an open access article distributed under 
      the terms of the Creative Commons Attribution License, which permits unrestricted 
      use, distribution, and reproduction in any medium, provided the original author 
      and source are credited.
FAU - Akhrif, Atae
AU  - Akhrif A
AD  - Department of Psychiatry and Psychotherapy, Medical Faculty, 
      Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
FAU - Romanos, Marcel
AU  - Romanos M
AD  - Department of Child and Adolescent Psychiatry, Center of Mental Health, 
      University Hospital Wuerzburg, Wuerzburg, Germany.
FAU - Peters, Katharina
AU  - Peters K
AD  - Department of Child and Adolescent Psychiatry, Center of Mental Health, 
      University Hospital Wuerzburg, Wuerzburg, Germany.
FAU - Furtmann, Ann-Kathrin
AU  - Furtmann AK
AD  - Department of Psychiatry and Psychotherapy, Medical Faculty, 
      Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
FAU - Caspers, Julian
AU  - Caspers J
AD  - Department of Diagnostic and Interventional Radiology, Medical Faculty, 
      Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
FAU - Lesch, Klaus-Peter
AU  - Lesch KP
AD  - Division of Molecular Psychiatry, Center of Mental Health, University of 
      Wuerzburg, Wuerzburg, Germany.
AD  - Department of Psychiatry and Neuropsychology, School for Mental Health and 
      Neuroscience, Maastricht University, Maastricht, The Netherlands.
FAU - Meisenzahl-Lechner, Eva M
AU  - Meisenzahl-Lechner EM
AD  - Department of Psychiatry and Psychotherapy, Medical Faculty, 
      Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
FAU - Neufang, Susanne
AU  - Neufang S
AUID- ORCID: 0000-0002-4927-2969
AD  - Department of Psychiatry and Psychotherapy, Medical Faculty, 
      Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
LA  - eng
SI  - Dryad/10.5061/dryad.d51c5b06x
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230427
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 1.14.16.4 (Tryptophan Hydroxylase)
RN  - EC 1.13.11.11 (Tryptophan Oxygenase)
RN  - EC 1.14.16.4 (TPH2 protein, human)
SB  - IM
MH  - Female
MH  - Humans
MH  - *Attention Deficit Disorder with Hyperactivity/genetics
MH  - DNA Methylation
MH  - Tryptophan Hydroxylase/genetics
MH  - Genotype
MH  - Brain/diagnostic imaging
MH  - Tryptophan Oxygenase/genetics
MH  - Polymorphism, Single Nucleotide
PMC - PMC10138254
COIS- The authors have declared that no competing interests exist.
EDAT- 2023/04/27 18:41
MHDA- 2023/05/01 06:41
PMCR- 2023/04/27
CRDT- 2023/04/27 13:35
PHST- 2022/10/15 00:00 [received]
PHST- 2023/02/22 00:00 [accepted]
PHST- 2023/05/01 06:41 [medline]
PHST- 2023/04/27 18:41 [pubmed]
PHST- 2023/04/27 13:35 [entrez]
PHST- 2023/04/27 00:00 [pmc-release]
AID - PONE-D-22-28504 [pii]
AID - 10.1371/journal.pone.0282813 [doi]
PST - epublish
SO  - PLoS One. 2023 Apr 27;18(4):e0282813. doi: 10.1371/journal.pone.0282813. 
      eCollection 2023.