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

Abstract

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.

No association between peripheral serotonin-gene-related DNA methylation and brain serotonin neurotransmission in the healthy and depressed state

“…Previous evidence supports an association between the CpG sites observed in our study and psychopathological features [ 7 , 16 , 48 ]. However, little is known about how peripheral DNA methylation of serotonin genes maps onto the brain serotonergic architecture.…”

“…SLC6A4 methylation percentages were estimated at four CpG sites (Table S2) that were previously linked to clinical phenotypes, including depressive symptoms [ 7 , 16 , 26 , 46 ], early-life adversities [ 7 ], recent environmental stress [ 15 ], antidepressant treatment outcome [ 20 , 21 ] and panic disorder [ 16 ]. TPH2 methylation was estimated at 6 CpG sites (Table S2) based on previous studies showing an association with gene expression ( 13 , 26 , 28 ), early life stress, depressive symptoms, antidepressant treatment outcome [ 23 , 24 , 47 ] and attention deficit hyperactivity disorder [ 48 ].…”

“…5-HTTLPR/rs25531 genotype was included in the statistical models including SLC6A4 methylation based on previous studies suggesting a combined effect of genotype and DNA methylation on 5-HTT transcription [ 13 , 17 ]. Similarly, TPH2 rs4570625 was included in the models evaluating TPH2 methylation [ 48 ]. Models evaluating associations between DNA methylation and 5-HT 4 binding also included information of 5-HTTLPR/rs25531 and BDNF rs6265, based on previous findings [ 58 ].…”