Patients with Neurofibromatosis Type 1 (NF1) frequently display symptoms resembling those of Attention Deficit/Hyperactivity Disorder (ADHD). Importantly, these disorders are characterised by distinct changes in the dopaminergic system, which plays an important role in timing performance and feedback-based adjustments in timing performance. In a transdiagnostic approach, we examine how far NF1 and ADHD show distinct or comparable profiles of timing performance and feedback-based adjustments in timing.

We examined time estimation and learning processes in healthy control children (HC), children with ADHD with predominantly inattentive symptoms and those with NF1 using a feedback-based time estimation paradigm.

Healthy controls consistently responded closer to the correct time window than both patient groups, were less variable in their reaction times and displayed intact learning-based adjustments across time. The patient groups did not differ from each other regarding the number of in-time responses. In ADHD patients, the performance was rather unstable across time. No performance changes could be observed in patients with NF1 across the entire task.

Children with ADHD and NF1 differ in feedback learning-based adjustments of time estimation processes. ADHD is characterised by behavioural fluctuations during the learning process. These are likely to be associated with inefficiencies in the dopaminergic system. NF1 is characterised by impairments of feedback learning which could be due to various neurotransmitter alterations occurring in addition to deficits in dopamine synthesis. Results show that despite the strong overlap in clinical phenotype and neuropsychological deficits between NF1 and ADHD, the underlying cognitive mechanisms are different.

A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE).

The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8–40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses.

When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10).

We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

Previous work suggests that reaction time variability (RTV) in attentional tasks, as a measure of cognitive stability, is associated with degree of Val loading in COMT Val158Met genotype, and that this association may be relevant for the aetiology of schizophrenia. This study examined (i) to what degree RTV pertaining to tasks of varying cognitive complexity would be associated with increased risk for schizophrenia and (ii) to what degree this would be mediated by Val loading.

COMT genotyping was investigated in a sample of 23 patients with schizophrenia, 33 first-degree relatives, and 21 controls. All participants performed the Flanker continuous performance test.

Schizophrenia liability was associated with number of correct trials of the Flanker test, but not with RTV, and this association was not mediated by COMT Val158Met genotype. Similarly, Met loading was associated with number of correct trials and with RTV, but this was not mediated by schizophrenia liability.

Associations between COMT Val158Met genotype and RTV do not appear to reflect transmission of schizophrenia liability in families. Differential associations with Val and Met alleles across studies suggest indirect effects through gene–gene interactions or the influence of a functional polymorphism near COMT Val158Met.

Increased reaction time variability (RTV) on cognitive tasks requiring a speeded response is characteristic of several psychiatric disorders. In attention deficit hyperactivity disorder (ADHD), the association with RTV is strong phenotypically and genetically, yet high RTV is not a stable impairment but shows ADHD-sensitive improvement under certain conditions, such as those with rewards. The state regulation theory proposed that the RTV difference score, which captures change from baseline to a rewarded or fast condition, specifically measures ‘state regulation’. By contrast, the interpretation of RTV baseline (slow, unrewarded) scores is debated. We aimed to investigate directly the degree of phenotypic and etiological overlap between RTV baseline and RTV difference scores.

We conducted genetic model fitting analyses on go/no-go and fast task RTV data, across task conditions manipulating rewards and event rate, from a population-based twin sample (n=1314) and an ADHD and control sibling-pair sample (n=1265).

Phenotypic and genetic/familial correlations were consistently high (0.72–0.98) between RTV baseline and difference scores, across tasks, manipulations and samples. By contrast, correlations were low between RTV in the manipulated condition and difference scores. A comparison across two different go/no-go task RTV difference scores (slow-fast/slow-incentive) showed high phenotypic and genetic/familial overlap (r = 0.75–0.83).

Our finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV. Given the statistical shortcomings of difference scores, we recommend the use of RTV baseline scores for most analyses, including genetic analyses.

Attention deficit hyperactivity disorder (ADHD) shows a strong phenotypic and genetic association with reaction time (RT) variability, considered to reflect lapses in attention. Yet we know little about whether this aetiological pathway is shared with other affected cognitive processes in ADHD, such as lower IQs or the generally slower responses (mean RTs). We aimed to address the question of whether a shared set of genes exist that influence RT variability, mean RT, IQ and ADHD symptom scores, or whether there is evidence of separate aetiological pathways.

Multivariate structural equation modelling on cognitive tasks data (providing RT data), IQ and ADHD ratings by parents and teachers collected on general population sample of 1314 twins, at ages 7–10 years.

Multivariate structural equation models indicated that the shared genetic influences underlying both ADHD symptom scores and RT variability are also shared with those underlying mean RT, with both types of RT data largely indexing the same underlying liability. By contrast, the shared genetic influences on ADHD symptom scores and RT variability (or mean RT) are largely independent of the genetic influences that ADHD symptom scores share with IQ.

The finding of unique aetiological pathways between IQ and RT data, but shared components between mean RT, RT variability and ADHD symptom scores, illustrates key influences in the genetic architecture of the cognitive and energetic processes that underlie the behavioural symptoms of ADHD. In addition, the multivariate genetic model fitting findings provide valuable information for future molecular genetic analyses.