The catecholamines dopamine and noradrenaline have been implicated in spontaneous low-frequency fluctuations in reaction time, which are associated with attention deficit hyperactivity disorder (ADHD) and subclinical attentional problems. The molecular genetic substrates of these behavioral phenotypes, which reflect frequency ranges of intrinsic neuronal oscillations (Slow-4: 0.027-0.073 Hz; Slow-5: 0.010-0.027 Hz), have not yet been investigated. In this study, we performed regression analyses with an additive model to examine associations between low-frequency fluctuations in reaction time during a sustained attention task and genetic markers across 23 autosomal catecholamine genes in a large young adult population cohort (n = 964), which yielded greater than 80% power to detect a small effect size (f(2) = 0.02) and 100% power to detect a small/medium effect size (f(2) = 0.15). At significance levels corrected for multiple comparisons, none of the gene variants were associated with the magnitude of low-frequency fluctuations. Given the study's strong statistical power and dense coverage of the catecholamine genes, this either indicates that associations between low-frequency fluctuation measures and catecholamine gene variants are absent or that they are of very small effect size. Nominally significant associations were observed between variations in the alpha-2A adrenergic receptor gene (ADRA2A) and the Slow-5 band. This is in line with previous reports of an association between ADRA2A gene variants and general reaction time variability during response selection tasks, but the specific association of these gene variants and low-frequency fluctuations requires further confirmation. Pharmacological challenge studies could in the future provide convergent evidence for the noradrenergic modulation of both general and time sensitive measures of intra-individual variability in reaction time.
Background. In psychiatric genetics research, the volume of ambivalent findings on gene-environment interactions (G x E) is growing at an accelerating pace. In response to the surging suspicions of systematic distortion, we challenge the notion of chance capitalization as a possible contributor. Beyond qualifying multiple testing as a mere methodological issue that, if uncorrected, leads to chance capitalization, we advance towards illustrating the potential benefits of multiple tests in understanding equivocal evidence in genetics literature. Method. We focused on the interaction between the serotonin-transporter-linked promotor region (5-HTTLPR) and childhood adversities with regard to depression. After testing 2160 interactions with all relevant measures available within the Dutch population study of adolescents TRAILS, we calculated percentages of significant (p < .05) effects for several subsets of regressions. Using chance capitalization (i.e. overall significance rate of 5% alpha and randomly distributed findings) as a competing hypothesis, we expected more significant effects in the subsets of regressions involving: 1) interview-based instead of questionnaire-based measures; 2) abuse instead of milder childhood adversities; and 3) early instead of later adversities. Furthermore, we expected equal significance percentages across 4) male and female subsamples, and 5) various genotypic models of 5-HTTLPR. Results. We found differences in the percentages of significant interactions among the subsets of analyses, including those regarding sex-specific subsamples and genetic modeling, but often in unexpected directions. Overall, the percentage of significant interactions was 7.9% which is only slightly above the 5% that might be expected based on chance. Conclusion. Taken together, multiple testing provides a novel approach to better understand equivocal evidence on G x E, showing that methodological differences across studies are a likely reason for heterogeneity in findings - but chance capitalization is at least equally plausible.
Peer cliques form an important context for the social development of adolescents. Although clique members are often similar in social status, also within cliques, status differences exist. How differences in social status between clique members are related to behaviors of its individual members is rather unknown. This study examined to what extent the relationship of individual social status (i.e., perceived popularity) with aggression and prosocial behavior depends on the level of internal clique hierarchy. The sample consists of 2674 adolescents (49.8% boys), with a mean age of 14.02. We focused specifically on physical and relational aggression, and practical and emotional support, because these behaviors have shown to be of great importance for social relationships and social standing among adolescents. The internal status hierarchy of cliques was based on the variation in individual social status between clique members (i.e., clique hierarchization) and the structure of status scores within a clique (pyramid shape, inverted pyramid, or equal distribution of social status scores) (i.e., clique status structure). The results showed that differences in aggressive and prosocial behaviors were particularly moderated by clique status structure: aggression was stronger related to individual social status in (girls') cliques where the clique status structure reflected an inverted pyramid with relatively more high status adolescents within the clique than low status peers, and prosocial behavior showed a significant relationship with individual social status, again predominantly in inverted pyramid structured (boys' and girls') cliques. Furthermore, these effects differed by types of gender cliques: the associations were found in same gender but not mixed-gender cliques. The findings stress the importance of taking into account internal clique characteristics when studying adolescent social status in relationship to aggression and prosociality.
Background. Increased intra-subject reaction time variability (RT-ISV) as coarsely measured by the standard deviation (RT-SD) has been associated with many forms of psychopathology. Low-frequency RT fluctuations, which have been associated with intrinsic brain rhythms occurring approximately every 15-40s, have been shown to add unique information for ADHD. In this study, we investigated whether these fluctuations also relate to attentional problems in the general population, and contribute to the two major domains of psychopathology: externalizing and internalizing problems. Methods. RT was monitored throughout a self-paced sustained attention task (duration: 9.1 ± 1.2 min) in a Dutch population cohort of young adults (n=1455, mean age: 19.0 ± 0.6 years, 55.1% girls). To characterize temporal fluctuations in RT, we performed direct Fourier Transform on externally validated frequency bands based on frequency ranges of neuronal oscillations: Slow-5 (0.010-0.027 Hz), Slow-4 (0.027-0.073 Hz), and three additional higher frequency bands. Relative magnitude of Slow-4 fluctuations was the primary predictor in regression models for attentional, internalizing and externalizing problems (measured by the Adult Self-Report questionnaire). Additionally, stepwise regression models were created to investigate (a) whether Slow-4 significantly improved the prediction of problem behaviors beyond the RT-SD and (b) whether the other frequency bands provided important additional information. Results. The magnitude of Slow-4 fluctuations significantly predicted attentional and externalizing problems and even improved model fit after modeling RT-SD first (R(2) change=0.6%, P<.01). Subsequently, adding Slow-5 explained additional variance for externalizing problems (R(2) change=0.4%, P<.05). For internalizing problems, only RT-SD made a significant contribution to the regression model (R(2)=0.5%, P<.01), that is, none of the frequency bands provided additional information. Conclusions. Low-frequency RT fluctuations have added predictive value for attentional and externalizing, but not internalizing problems beyond global differences in variability. This study extends previous findings in clinical samples of children with ADHD to adolescents from the general population and demonstrates that deconstructing RT-ISV into temporal components can provide more distinctive information for different domains of psychopathology.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
The following hypotheses were tested in a longitudinal, population-based study: (1) Attention deficit hyperactivity disorder (ADHD) symptoms are associated with peer dislike and victimisation; (2) Peer dislike and victimisation increase the risk for subsequent depression; and (3) The effect of ADHD symptoms on depression is partly mediated through peer dislike and victimisation. Gender differences in mediating pathways through peer dislike and victimisation to depression were additionally explored. The Child Behaviour Checklist (CBCL), Youth Self Report (YSR) and Teacher's Checklist of Pathology (TCP) assessed ADHD symptoms in 728 adolescents. Peer nominations were used to assess peer dislike and victimisation. The Composite International Diagnostic Interview (CIDI) was used to assess depression. Effects of peer dislike, victimisation, and ADHD symptoms on depression were modelled using Cox regression. ADHD symptoms were associated with peer dislike (rs = 0.17, p < 0.001) and victimisation (rs = 0.11, p = 0.001). Dislike, victimisation, and ADHD symptoms increased risk for depression. Risk for depression associated with victimisation and ADHD symptoms reduced with time. Dislike and victimisation mediated 7 % of the effect of ADHD symptoms on depression. Pathways through dislike and victimisation were present in girls but not in boys. Peer dislike and victimisation explain, to a limited extent, the prospective association between ADHD and depression, particularly in girls.
TRAILS consists of a population cohort (N=2230) and a clinical cohort (N=543), both of which were followed from about age 11 years onwards. To date, the population cohort has been assessed five times over a period of 11 years, with retention rates ranging between 80% and 96%. The clinical cohort has been assessed four times over a period of 8 years, with retention rates ranging between 77% and 85%. Since the IJE published a cohort profile on the TRAILS in 2008, the participants have matured from adolescents into young adults. The focus shifted from parents and school to entry into the labour market and family formation, including offspring. Furthermore, psychiatric diagnostic interviews were administered, the database was linked to a Psychiatric Case Registry, and the availability of genome-wide SNP variations opened the door to genome-wide association studies regarding a wide range of (endo)phenotypes. With some delay, TRAILS data are available to researchers outside the TRAILS consortium without costs; access can be obtained by submitting a publication proposal (see www.trails.nl).
© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.