COMT x DRD4 epistasis impacts prefrontal cortex function underlying response control.

The prefrontal cortex plays a major role in cognitive control, but it is unclear how single genes and gene-gene interactions (genetic epistasis) impact neural and behavioral phenotypes. Both dopamine (DA) availability ("inverted U-model") and excitatory versus inhibitory DA receptor stimulation ("dual-state theory") have been linked to important principles of prefrontal processing. Catechol-O-methyltransferase (COMT; Val158Met) and DA D4-receptor (DRD4; 48 bp VNTR) genotypes were analyzed for effects on behavioral and neural correlates of prefrontal response control (NoGo-anteriorization, NGA) using a Go-NoGo task and electroencephalography (114 controls and 181 patients with attention-deficit/hyperactivity disorder).  DRD4 and COMT epistatically interacted on the NGA, whereas single genes and diagnosis showed no significant impact. Subjects with presumably relatively increased D4-receptor function (DRD4: no 7R-alleles) displayed an inverted U-relationship between the NGA and increasing COMT-dependent DA levels, whereas subjects with decreased D4-sensitivity (7R) showed a U-relationship. This interaction was supported by 7R-allele dose effects and mirrored by reaction time variability (non-significant after multiple testing correction). Combining previous theories of prefrontal DA functioning, neural stability at intermediate DA levels may be accompanied by the risk of overly decreased neural flexibility if inhibitory DA receptor function is additionally decreased. Our findings might help to disentangle the genetic basis of dopaminergic mechanisms underlying prefrontal (dys)function.

Functional variants of TSPAN8 are associated with bipolar disorder and schizophrenia.

Tetraspanins affect protein trafficking and are known to influence a wide variety of physiologic processes. Recently, single nucleotide polymorphisms (SNPs) of the tetraspanin gene TSPAN8 were found among the best ranked markers of genome wide association studies on bipolar disorder (BPD) (rs1705236) and type-2 diabetes, but functional consequences remained largely unknown. In the present study, we examined 13 tagging SNPs covering the TSPAN8 gene, the intronic TSPAN8 SNP rs1705236 as well as two non-synonymous (ns) SNPs in schizophrenia (SCZ) and BPD samples. In our analysis setting, we were not able to replicate the association of rs1705236 with BPD, nor did we find an association with SCZ. In the TSPAN8 upstream transcriptional control region however, we found rs4500567 to be associated with BPD. In contrast, in SCZ the nsSNP rs3763978 was associated with disease. The significance of both associations withstood conservative Bonferroni correction. In an attempt to link the polymorphisms to functional consequences, we performed an allele-specific in silico mapping of transcription factor binding sites around rs4500567 and predicted the tolerance of the Gly73Ala exchange caused by rs3763978. The results argue for a differential promoter activity specific for the variant associated with BPD, but impaired protein functionality in SCZ. This suggests that TSPAN8 contributes to both diseases, yet with different underlying mechanisms: regulatory versus structural. Similar phenomena might also occur in other risk genes for both BPD and SCZ, providing a molecular basis for the genetic overlap of both entities.

Common variants in the TPH1 and TPH2 regions are not associated with persistent ADHD in a combined sample of 1,636 adult cases and 1,923 controls from four European populations.

The tryptophan hydroxylase 1 and 2 (TPH1 and TPH2) genes encode the rate-limiting enzymes in the serotonin biosynthesis. Genetic variants in both genes have been implicated in several psychiatric disorders. For attention-deficit/hyperactivity disorder (ADHD) in children, the results are conflicting, and little is known about their role in adult ADHD patients. We therefore first genotype-tagged all common variants within both genes in a Norwegian sample of 451 patients with a diagnosis of adult ADHD and 584 controls. Six of the single nucleotide polymorphisms (SNPs) were subsequently genotyped in three additional independent European Caucasian samples of adult ADHD cases and controls from the International Multicenter persistent ADHD Collaboration (IMpACT). None of the SNPs reached formal study-wide significance in the total meta-analysis sample of 1,636 cases and 1,923 controls, despite having a power of >80% to detect a variant conferring an OR = 1.25 at P = 0.001 level. Only the TPH1 SNP rs17794760 showed nominal significance [OR = 0.84 (0.71-1.00), P = 0.05]. In conclusion, in the single largest ADHD genetic study of TPH1 and TPH2 variants presented to date (n = 3,559 individuals), we did not find consistent evidence for a substantial effect of common genetic variants on persistent ADHD.

Diminished prefrontal oxygenation with normal and above-average verbal fluency performance in adult ADHD.

Attention-Deficit/Hyperactivity Disorder (ADHD) in adults is associated with deficits in executive functions such as verbal fluency. Functional near-infrared spectroscopy offers the possibility to measure brain activity during verbal fluency in psychiatric patients due to low susceptibility to movements artefacts. Fourteen patients with mainly combined ADHD subtype and 14 healthy controls matched for age, gender, handedness, education level, and intelligence showed equal performance in phonological verbal fluency and higher performance in semantical verbal fluency in comparison to the controls. On the level of brain function indicated by concentration changes of oxygenated and deoxygenated haemoglobin, both groups showed inferior frontal brain activity during both tasks. ADHD patients had a lower magnitude of oxygenation and a significant negative correlation of brain activity with performance, i.e. higher brain activity was associated with lower performance. These results might be interpreted as a lack of disease related deficits, as an economical recruitment of cognitive resources, or - more likely - as an expression of a benefit in the patient group. High verbal competence in our samples could contribute to these findings. One speculative and post hoc explanation aims at the clinically well-known phenomenon of hyperfocusing in patients with ADHD.

Working memory and response inhibition as one integral phenotype of adult ADHD? A behavioral and imaging correlational investigation.

OBJECTIVE: It is an open question whether working memory (WM) and response inhibition (RI) constitute one integral phenotype in attention deficit hyperactivity disorder (ADHD). METHOD: The authors investigated 45 adult ADHD patients and 41 controls comparable for age, gender, intelligence, and education during a letter n-back and a stop-signal task, and measured prefrontal oxygenation by means of functional near-infrared spectroscopy. RESULTS: The authors replicated behavioral and cortical activation deficits in patients compared with controls for both tasks and also for performance in both control conditions. In the patient group, 2-back performance was correlated with stop-signal reaction time. This correlation did not seem to be specific for WM and RI as 1-back performance was correlated with go reaction time. No significant correlations of prefrontal oxygenation between WM and RI were found. CONCLUSION: The authors' findings do not support the hypothesis of WM and RI representing one integral phenotype of ADHD mediated by the prefrontal cortex.

Cross-disorder analysis of bipolar risk genes: further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD.

Recently, several genome-wide association studies (GWAS) on bipolar disorder (BPD) suggested novel risk genes. However, only few of them were followed up and further, the specificity of these genes is even more elusive. To address these issues, we genotyped SNPs in ANK3, CACNA1C, CMTM8, DGKH, EGFR, and NPAS3, which were significantly associated with BPD in previous GWAS, in a sample of 380 BPD patients. Replicated SNPs were then followed up in patients suffering from unipolar depression (UPD; n=387) or adult attention-deficit/hyperactivity disorder (aADHD; n=535). While we could not confirm an association of ANK3, CACNA1C, and EGFR with BPD, 10 SNPs in DGKH, CMTM8, and NPAS3 were nominally associated with disease, with two DGKH markers surviving correction for multiple testing. When these were followed up in UPD and aADHD, seven DGKH SNPs were also associated with UPD, while one SNP each in NPAS3 and CMTM8 and four in DGKH were linked to aADHD. Furthermore, a DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with all disorders tested, while the complementary AGC haplotype was protective. The corresponding haploblock spans a 27-kb region covering exons coding for amino acids 65-243, and thus might include functional variants yet to be identified. We demonstrate an association of DGKH with BPD, UPD, and aADHD by applying a two-stage design. These disorders share the feature of mood instability, so that this phenotype might be associated with genetic variation in DGKH.

Neural correlates of performance monitoring in adult patients with attention deficit hyperactivity disorder (ADHD).

INTRODUCTION: In this study, the neural correlates of error processing in adult patients with attention deficit hyperactivity disorder (ADHD) are to be investigated for the first time. Recent studies in children with ADHD suggested, with some inconsistencies, deficits in error processing. Based on an analogue study with students, we hypothesized that ADHD patients show reduced amplitudes in the event-related potential (ERP) of the Pe (error positivity) but normal amplitudes of the ERN (error-related negativity) after incorrect responses. METHOD: In this study we investigated 34 adult ADHD patients and 34 healthy controls with a modified version of the Eriksen flanker task while recording the neural activity with 26 scalp EEG electrodes. Patients discontinued all medication at least 3 days prior to investigation. Age was included as a control variable for the statistical analyses. RESULTS AND CONCLUSION: As hypothesized, we found reduced Pe amplitudes, but also reduced ERN values, in ADHD patients. Importantly, theses differences as well as the deficits in behavioural performance were mainly detectable in the younger subsample, but not in the elderly subsample. Our results indicate that adult ADHD patients are characterized by deficits in error processing, which vanish with age.

Dopamine transporter (SLC6A3) genotype impacts neurophysiological correlates of cognitive response control in an adult sample of patients with ADHD.

Studies provide ample evidence for a dysfunction in dopaminergic neurotransmission in Attention-Deficit/Hyperactivity Disorder (ADHD). In that respect, a common variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region (UTR) of the dopamine transporter gene (SLC6A3) has been repeatedly associated with the disorder. Here, we examined the influence of the common 9- and 10-repeat alleles of SLC6A3 on prefrontal brain functioning and cognitive response control in a large sample of adult ADHD patients (n=161) and healthy controls (n=109). To this end, we inspected a neurophysiological marker of cognitive response control (NoGo anteriorization, NGA) elicited by means of a Go-NoGo task (continuous performance test, CPT). Within the group of ADHD patients, nine-repeat allele carriers showed significantly reduced NGA, whereas no influence of SLC6A3 genotype was observed in the control group. In contrast to previous association studies of children, the nine-repeat-not the 10-repeat-allele was associated with functional impairments in our sample of adult ADHD patients. Our findings confirm a significant effect of the SLC6A3 genotype on the neurophysiological correlates of cognitive response control in ADHD, and indicate that still to-be-identified age-related factors are important variables modulating the effect of genetic factors on endophenotypes.

Early attentional deficits in an attention-to-prepulse paradigm in ADHD adults.

Adults with attention-deficit/hyperactivity disorder (ADHD) were examined for early and late attentional processes as a function of controlled attention. The test paradigm was the attentional modulation of prepulse inhibition (PPI; early controlled attentional processing) and prepulse facilitation (PPF; late controlled attentional processing). In 49 patients and 49 controls, the authors measured acoustic startle responses to 96-dB startle pulses preceded 120, 240 (for PPI), 2,000, and 4,500 (for PPF) ms by a 68-dB prepulse noise. Geometric figures signaled that prepulses were to be ignored or attended to (automatic vs. controlled attention). ADHD patients exhibited deficits in prepulse modulation, but these reflected an interaction of controlled attention and time of information processing. Normal PPI and PPF occurred under all conditions except for controlled attentional modulation of PPI. Attention deficits in ADHD patients may reflect not general derangements in information processing or ability to attend but, rather, selective disturbances of controlled attention during early information processing.

Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4-5% in children and 1-4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3'-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3'-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.

Emotional deficits in adult ADHD patients: an ERP study.

This study examined general deficits in positive stimuli evaluation in adults with Attention Deficit Hyperactivity Disorder (ADHD). We investigated the event-related potentials to positive, negative and neutral pictures in 32 adults with ADHD and 32 control subjects. For this study we measured 21 electrodes placed in accordance with the international 10-20 system and calculated the early posterior negativity (EPN), which physiologically is characterized by more negative values for emotional as compared to neutral stimuli. We found significantly reduced EPN values for the ADHD patients compared to the healthy controls, but only in the positive stimuli condition, without any significant differences in the negative stimuli condition. Our data indicate that ADHD patients show less reactivity to positive visual stimuli which might be relevant in the context of described dysfunctions of the motivational-reward system in ADHD.

Abnormal affective responsiveness in attention-deficit/hyperactivity disorder: subtype differences.

BACKGROUND: Emotional-motivational dysfunctions likely contribute to attention-deficit/hyperactivity disorder (ADHD), especially to hyperactive and impulsive symptoms. This study examined the affective modulation of the startle reflex in a large sample of ADHD patients. The aim was to compare subtypes of ADHD. METHODS: One hundred ninety-seven unmedicated adult ADHD patients (127 combined type [ADHD-C]; 50 inattentive type [ADHD-I]; 20 hyperactive-impulsive type [ADHD-HI]) and 128 healthy control subjects were examined. The affect-modulated startle response as well as valence and arousal ratings were assessed for pleasant, neutral, and unpleasant picture stimuli. RESULTS: Control subjects exhibited startle response attenuation and potentiation by pleasant and unpleasant pictures, respectively. In ADHD-HI, startle response was not attenuated by pleasant and not potentiated by unpleasant stimuli. In ADHD-C, startle response was not attenuated by pleasant pictures, and ADHD-I responded similar to control subjects but startle response was attenuated to a lesser degree by pleasant stimuli. The ADHD-HI group rated all pictures as more positive, and male ADHD-HI rated unpleasant stimuli as less arousing. CONCLUSIONS: This is the first study to assess the affect-modulated startle response in ADHD. It confirms emotional dysfunctions in these patients; all subtypes showed more or less diminished emotional reactions to pleasant stimuli. The hyperactive-impulsive type was also marked by blunted reactions to unpleasant stimuli. Results suggest that response patterns to emotional cues or reward may help to differentiate ADHD subtypes. Blunted emotional reactivity is especially pronounced in ADHD patients with symptoms of hyperactivity and impulsivity (ADHD-C, ADHD-HI).