Ruud B. Minderaa

Cohort Profile: The Dutch ‘TRacking Adolescents’ Individual Lives’ Survey’; TRAILS

Mental disorders account for one-fifth of the total burden of disease in the Western world, 1 and, as such, should require due attention from the international epidemiological research community. Good quality research on the aetiology and course of psychopathology in the population is impossible without reliable and valid data from long-term longitudinal cohort studies. Research on psychopathology in adolescence is important both from a scientific point of view and from the point of view of prevention and public health policy. Adolescence is characterized by major biological, psychological and social challenges and opportunities, where interaction between the individual and environment is intense, and developmental pathways are set in motion or become established. 2–4 Furthermore, adolescent psychopathology can have important consequences for education, relationships and socioeconomic achievement in later life. 5–7 These characteristics of adolescence do not only set high demands for cohort studies aiming to capture the most salient aspects of developmental pathways, they also ensure a great gain in empirical knowledge and an invaluable source of information for public health policy from such studies. In order to fully benefit from this potential, a multidisciplinary approach is essential.

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior.

Platelet Serotonin Levels in Pervasive Developmental Disorders and Mental Retardation: Diagnostic Group Differences, Within-Group Distribution, and Behavioral Correlates

OBJECTIVEnTo investigate group differences, the within-group distributions, and the clinical correlates of platelet serotonin (5-HT) levels in pervasive developmental disorders (PDD).nnnMETHODnPlatelet 5-HT levels were measured in Dutch children and young adults, recruited from 2001 through 2003, with PDD (autism, Aspergers, and PDD-not otherwise specified [PDD-NOS]; n = 81) or with mental retardation (MR; n = 54) but without PDD, and in normal controls (n = 60). The distribution of platelet 5-HT levels was assessed using mixture-modeling analyses. Relationships between platelet 5-HT levels and a full range of demographic, clinical, and behavioral variables were examined.nnnRESULTSnGroup mean (+/- SD) platelet 5-HT levels (nmol/10 platelets) were significantly higher in the autistic (4.51 +/- 1.61, n = 33) and PDD-NOS (4.90 +/- 1.54, n = 43) groups compared to the MR (3.48 +/- 1.33, n = 54) or the normal control (3.58 +/- 1.08, n = 60) groups (F4,190 = 9.35, p <.001). Platelet 5-HT values in the combined PDD group showed a bimodal distribution, and an empirical cutpoint for hyperserotonemia was determined. None of the behavioral variables examined was significantly associated with platelet 5-HT levels.nnnCONCLUSIONSnThe platelet hyperserotonemia of autism was replicated in Dutch subjects. Platelet 5-HT levels were also increased in PDD-NOS, while no elevation was seen in MR. Platelet 5-HT levels appeared to be bimodally distributed in the PDD group, with an apparent hyperserotonemic subgroup.

Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA

Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic–pituitary–adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.

DSM-IV Combined Type ADHD Shows Familial Association With Sibling Trait Scores: A Sampling Strategy For QTL Linkage

Attention deficit hyperactivity disorder (ADHD) is a discrete clinical syndrome characterized by the triad of inattention, hyperactivity, and impulsivity in the context of marked impairments. Molecular genetic studies have been successful in identifying genetic variants associated with ADHD, particularly with DSM‐IV inattentive and combined subtypes. Quantitative trait locus (QTL) approaches to linkage and association mapping have yet to be widely used in ADHD research, although twin studies investigating individual differences suggest that genetic liability for ADHD is continuously distributed throughout the population, underscoring the applicability of quantitative dimensional approaches. To investigate the appropriateness of QTL approaches, we tested the familial association between 894 probands with a research diagnosis of DSM‐IV ADHD combined type and continuous trait measures among 1,135 of their siblings unselected for phenotype. The sibling recurrence rate for ADHD combined subtype was 12.7%, yielding a sibling recurrence risk ratio (λsib) of 9.0. Estimated sibling correlations around 0.2–0.3 are similar to those estimated from the analysis of fraternal twins in population twin samples. We further show that there are no threshold effects on the sibling risk for ADHD among the ADHD probands; and that both affected and unaffected siblings contributed to the association with ADHD trait scores. In conclusion, these data confirm the main requirement for QTL mapping of ADHD by demonstrating that narrowly defined DSM‐IV combined type probands show familial association with dimensional ADHD symptom scores amongst their siblings.

Internalizing and externalizing problems in adolescence: general and dimension-specific effects of familial loadings and preadolescent temperament traits.

BACKGROUNDnWe investigated the links between familial loading, preadolescent temperament, and internalizing and externalizing problems in adolescence, hereby distinguishing effects on maladjustment in general versus dimension-specific effects on either internalizing or externalizing problems.nnnMETHODnIn a population-based sample of 2230 preadolescents (10-11 years) familial loading (parental lifetime psychopathology) and offspring temperament were assessed at baseline by parent report, and offspring psychopathology at 2.5-years follow-up by self-report, teacher report and parent report. We used purified measures of temperament and psychopathology and partialled out shared variance between internalizing and externalizing problems.nnnRESULTSnFamilial loading of internalizing psychopathology predicted offspring internalizing but not externalizing problems, whereas familial loading of externalizing psychopathology predicted offspring externalizing but not internalizing problems. Both familial loadings were associated with Frustration, low Effortful Control, and Fear. Frustration acted as a general risk factor predicting severity of maladjustment; low Effortful Control and Fear acted as dimension-specific risk factors that predicted a particular type of psychopathology; whereas Shyness, High-Intensity Pleasure, and Affiliation acted as direction markers that steered the conditional probability of internalizing versus externalizing problems, in the event of maladjustment. Temperament traits mediated one-third of the association between familial loading and psychopathology. Findings were robust across different composite measures of psychopathology, and applied to girls as well as boys.nnnCONCLUSIONSnWith regard to familial loading and temperament, it is important to distinguish general risk factors (Frustration) from dimension-specific risk factors (familial loadings, Effortful Control, Fear), and direction markers that act as pathoplastic factors (Shyness, High-Intensity Pleasure, Affiliation) from both types of risk factors. About one-third of familial loading effects on psychopathology in early adolescence are mediated by temperament.

How unspecified are disorders of children with a pervasive developmental disorder not otherwise specified ? A study of social problems in children with PDD-NOS and adhd

Abstractu2002This study examines possible differences and similarities between social behaviour problems in children with problems classified as pervasive developmental disorder not otherwise specified (PDD-NOS) and a group of children with problems classified as ADHD, as measured by parent questionnaires. The instruments involved were the CBCL (Child Behaviour Checklist), the ABC (Autism Behaviour Checklist) and a new instrument: the CSBQ (Childrens Social Behaviour Questionnaire). In comparing the PDD-NOS group and the ADHD group, the results show that, according to parent reports, both groups have severe problems in executing appropriate social behaviour, but the PDD-NOS group can be distinguished from the ADHD group by the nature and the extent of these problems. The PDD-NOS group had significantly more social problems (as measured by the CBCL Social scale), withdrawn problems (as measured by the CBCL Withdrawn scale) and PDD-specific problems (as measured on the ABC Relating scale, the ABC Language scale, the CSBQ total score, the CSBQ Social Interaction scale and CBSQ Communication scale). In addition, although the descriptions of the social problems are global, i.e. on scale level, the results also show that the social problems of PDD-NOS children can be positively formulated and described as at least including severe social interaction problems, withdrawn behaviours and communication problems.

Error and feedback processing in children with ADHD and children with Autistic Spectrum Disorder: An EEG event-related potential study

OBJECTIVEnPerformance monitoring was investigated in typically developing (TD) children, children with Autistic Spectrum Disorder (ASD), and Methylphenidate (Mph)-treated and medication-free children with Attention Deficit Hyperactivity Disorder (ADHD).nnnMETHODSnSubjects performed a feedback-based learning task. Event-related Potentials (ERPs) time locked to responses and feedback were derived from the EEG.nnnRESULTSnCompared to the TD and ASD groups, the medication-free ADHD group showed a decreased response-locked Error Related Negativity (ERN) and error Positivity (Pe), particularly as learning progressed throughout the task. Compared to the medication-free ADHD group, the Methylphenidate-treated group showed a normalised Pe. All clinical groups showed or tended to show a decreased feedback-locked late positive potential to negative feedback.nnnCONCLUSIONSnThe ERPs suggest that medication-free children with ADHD, but not with ASD, have a diminished capacity to monitor their error responses when they are learning by performance feedback. This capacity partially normalises in Mph-treated children with ADHD. Both children with ADHD and children with ASD are suggested being compromised in affective feedback processing.nnnSIGNIFICANCEnThis study shows that measuring ERPs of error and feedback processing is a useful method for (1) dissociating ADHD from ASD and (2) elucidating medication effects in ADHD on component processes of performance monitoring.

Diagnosing Autism Spectrum Disorders in Adults: the Use of Autism Diagnostic Observation Schedule (ADOS) Module 4

Autism Diagnostic Observation Schedule (ADOS) module 4 was investigated in an independent sample of high-functioning adult males with an autism spectrum disorder (ASD) compared to three specific diagnostic groups: schizophrenia, psychopathy, and typical development. ADOS module 4 proves to be a reliable instrument with good predictive value. It can adequately discriminate ASD from psychopathy and typical development, but is less specific with respect to schizophrenia due to behavioral overlap between autistic and negative symptoms. However, these groups differ on some core items and explorative analyses indicate that a revision of the algorithm in line with Gotham et al. (J Autism Dev Disord 37: 613–627, 2007) could be beneficial for discriminating ASD from schizophrenia.

High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.

Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family.