Sleep disturbances in ADHD: investigating the contribution of polygenic liability for ADHD and sleep-related phenotypes

Sleep disturbances are common in attention deficit hyperactivity disorder (ADHD) and associated with poor outcomes. We tested whether, in children with ADHD, (1) polygenic liability for sleep phenotypes is over- or under-transmitted from parents, (2) this liability is linked to comorbid sleep disturbances, and (3) ADHD genetic risk is associated with comorbid sleep disturbances. We derived polygenic scores (PGS) for insomnia, chronotype, sleep duration, and ADHD, in 758 children (5–18 years old) diagnosed with ADHD and their parents. We conducted polygenic transmission disequilibrium tests for each sleep PGS in complete parent–offspring ADHD trios (N = 328) and an independent replication sample of ADHD trios (N = 844). Next, we tested whether insomnia, sleep duration, and ADHD PGS were associated with co-occurring sleep phenotypes (hypersomnia, insomnia, restless sleep, poor sleep quality, and nightmares) in children with ADHD. Children’s insomnia and chronotype PGS did not differ from mid-parent average PGS but long sleep duration PGS were significantly over-transmitted to children with ADHD. This was supported by a combined analysis using the replication sample. Insomnia, sleep duration, and ADHD PGS were not associated with comorbid sleep disturbances. There is weak evidence that children with ADHD over-inherit polygenic liability for longer sleep duration and do not differentially inherit polygenic liability for insomnia or chronotype. There was insufficient evidence that childhood sleep disturbances were driven by polygenic liability for ADHD or sleep traits, suggesting that sleep disturbances in ADHD may be aetiologically different to general population sleep phenotypes and do not index greater ADHD genetic risk burden.

Development and Validation of a Multi-Dimensional Measure of Activity-Based Working Behaviors

Most work on activity-based working centers on the physical environment and digital technologies enabling flexible working. While important, we believe the key components for implementing activity-based working are employee and manager behaviors. To measure the degree of enactment of activity-based work, based on workshops with experienced practitioners as well as previous literature, we have developed and validated a behavior-focused measure of activity-based working behaviors. In our initial sample (Sample 1, N = 234), three subscales were identified: task – environment crafting, workday planning, and social needs prioritization. In the replication sample (Sample 2, N = 434), this model also showed adequate fit. Moreover, task – environment crafting was related to general health and lower stress in sample 1 (multi-organization sample), but not in the single-organization sample (sample 2). Workday planning was associated with higher concentration in both samples and in the second sample with general health and work engagement; the latter was also related to social needs prioritization.

Regret, Self-regulatory Abilities, and Well-Being: Their Intricate Relationships

Emotions, like regret, have been heralded as instruments of self-regulation, by instigating reflection, learning and feedback for betterment and thus increasing well-being. Yet, this view neglects taking the frequency of regret into consideration. Frequently experiencing regret may instead be a sign of repeatedly failing to achieve betterment. Previous work has shown that people who experience regret often have lower life satisfaction. We suggest that, by itself, the reflective function of regret is not enough to lead to betterment. Rather, in addition to regret, self-regulatory abilities are needed. In the absence of these abilities, the reflective function of regret does not turn off but is likely to lead to frequent episodes of regret and turn into counter-productive rumination, reducing rather than increasing well-being. We tested these possibilities in two studies. In Study 1, reports were administered about regret frequency, self-regulatory abilities, and life satisfaction in 388 US adults (54.6% males; Mage = 35, SD = 10). In the preregistered Study 2, the same instruments were administered in a replication sample of 470 British adults (22.1% males; Mage = 36, SD = 12). In both studies, low self-regulatory abilities were associated with higher regret frequency, which in turn, was associated with poorer life satisfaction. Moreover, in both studies, the negative association between regret frequency and life satisfaction was explained by ruminative brooding styles. In sum, the positive reflective function of regret for well-being cannot stand alone, but needs self-regulatory abilities. Without these abilities, regret experience is frequent and its reflective function turns into brooding rumination that negatively affects well-being.

Evidence from imaging resilience genetics for a protective mechanism against schizophrenia in the ventral visual pathway

Recently, the first genetic variants conferring resilience to schizophrenia have been identified. However, the neurobiological mechanisms underlying their protective effect remain unknown. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects in schizophrenia resilience. Here, we test the hypothesis that comparable changes can emerge from schizophrenia resilience genes. To this end, we used structural magnetic resonance imaging to investigate the effects of a schizophrenia polygenic resilience score (PRSResilience) on cortical morphology (discovery sample: n=101; UK Biobank replication sample: n=33,224). We observed positive correlations between PRSResilience and cortical volume in the fusiform gyrus, a central hub within the ventral visual pathway. Our findings indicate that resilience to schizophrenia arises partly from genetically mediated enhancements of visual processing capacities for social and non-social object information. This implies an important role of visual information processing for mitigating schizophrenia risk, which might also be exploitable for early intervention studies.

Weak Association Between the Glutamate Decarboxylase 1 Gene (GAD1) and Schizophrenia in Han Chinese Population

ObjectivesSchizophrenia (SZ) is a complex psychiatric disorder with high heritability, and genetic components are thought to be pivotal risk factors for this illness. The glutamate decarboxylase 1 gene (GAD1) was hypothesized to be a candidate risk locus for SZ given its crucial role in the GABAergic neurotransmission system, and previous studies have examined the associations of single nucleotide polymorphisms (SNPs) spanning the GAD1 gene with SZ. However, inconsistent results were obtained. We hence examined the associations between GAD1 SNPs and SZ in two independent case-control samples of Han Chinese ancestry.Materials and MethodsTwo Han Chinese SZ case-control samples, referred as the discovery sample and the replication sample, respectively, were recruited for the current study. The discovery sample comprised of 528 paranoid SZ cases (with age of first onset ≥ 18) and 528 healthy controls; the independent replication sample contained 1,256 early onset SZ cases (with age of first onset < 18) and 2,661 healthy controls. Logistic regression analysis was performed to examine the associations between GAD1 SNPs and SZ.ResultsTen SNPs covering GAD1 gene were analyzed in the discovery sample, and two SNPs showed nominal associations with SZ (rs2241165, P = 0.0181, OR = 1.261; rs2241164, P = 0.0225, OR = 1.219). SNP rs2241164 was also nominally significant in the independent replication sample (P = 0.0462, OR = 1.110), and the significance became stronger in a subsequent meta-analysis combining both discovery and replication samples (P = 0.00398, OR = 1.138). Nevertheless, such association could not survive multiple corrections, although the effect size of rs2241164 was comparable with other SZ risk loci identified in genome-wide association studies (GWAS) in Han Chinese population. We also examined the associations between GAD1 SNPs and SZ in published datasets of SZ GWAS in East Asians and Europeans, and no significant associations were observed.ConclusionWe observed weak associations between GAD1 SNPs and risk of SZ in Han Chinese populations. Further analyses in larger Han Chinese samples with more detailed phenotyping are necessary to elucidate the genetic correlation between GAD1 SNPs and SZ.

Scan Once, Analyse Many: Using Large Open-Access Neuroimaging Datasets to Understand the Brain

We are now in a time of readily available brain imaging data. Not only are researchers now sharing data more than ever before, but additionally large-scale data collecting initiatives are underway with the vision that many future researchers will use the data for secondary analyses. Here I provide an overview of available datasets and some example use cases. Example use cases include examining individual differences, more robust findings, reproducibility–both in public input data and availability as a replication sample, and methods development. I further discuss a variety of considerations associated with using existing data and the opportunities associated with large datasets. Suggestions for further readings on general neuroimaging and topic-specific discussions are also provided.

Neurocognitive Heterogeneity in Social Anxiety Disorder: The Role of Self-Referential Processing and Childhood Maltreatment

Social anxiety disorder (SAD) is characterized by negative self-beliefs and altered brain activation in the default-mode network (DMN). However, the extent to which there is neurocognitive heterogeneity in SAD remains unclear. We had two independent samples of patients perform a self-referential encoding task and complete self-reports of childhood maltreatment, subjective well-being, and emotion regulation. In the replication sample, we also measured DMN activation using functional MRI. We used k-means clustering, which revealed two distinct subgroups of patients with SAD in the discovery sample. Cluster 1 demonstrated higher levels of negative self-referential trait endorsement, lower levels of positive self-referential trait endorsement, and significantly higher levels of childhood emotional maltreatment, lower subjective well-being, and altered emotion-regulation-strategy use. A similar pattern was observed in the replication sample, which further demonstrated higher DMN activation during negative trait judgments in Cluster 1. Participants in the SAD clusters, from both the discovery and replication samples, were significantly distinct from samples of control participants. These findings reveal neurocognitive heterogeneity in SAD and its relationship to emotional maltreatment.

Prenatal exposure to paternal smoking and likelihood for autism spectrum disorder

Genetics, environment, and their interactions impact autism spectrum disorder etiology. Smoking is a suspected autism spectrum disorder risk factor due to biological plausibility and high prevalence. Using two large epidemiological samples, we examined whether autism spectrum disorder was associated with prenatal paternal smoking in a Discovery sample ( N = 10,245) and an independent Replication sample ( N = 29,773). Paternal smoking was retrospectively assessed with questionnaires. Likelihood of having autism spectrum disorder was estimated with the Autism Spectrum Screening Questionnaire at three levels: low (<10), intermediate (10–14), and high (⩾15). Ordinal regression was used to examine the relationship between prenatal paternal smoking and likelihood of having autism spectrum disorder, adjusting for confounders. A total of 36.5% of Discovery sample fathers and 63.3% of Replication sample fathers smoked during the pregnancy period; 7% of the Replication sample smoker fathers smoked during the pre-conception period but quit during pregnancy period. Discovery sample prenatal paternal smoking significantly increased the likelihood of having autism spectrum disorder in their offspring (adjusted odds ratio=1.27). This was confirmed in the Replication sample with adjusted odds ratio of 1.15 among smoking pre-conception period + pregnancy period fathers; 14.4% and 11.1% increased high likelihood of autism spectrum disorder was attributable to prenatal paternal smoking in Discovery sample and Replication sample, respectively. Smoking prevention, especially in pregnancy planning, may decrease autism spectrum disorder risk in offspring. Lay abstract What is Already Known about This Subject: Genetics, (including de novo mutations), environmental factors (including toxic exposures), and their interactions impact autism spectrum disorder etiology. Paternal smoking is a candidate risk for autism spectrum disorder due to biological plausibility, high prevalence, and potential intervention. What This Study Adds: This original study and its replication confirms that paternal factors can substantially contribute to autism spectrum disorder risk for their offspring. It specifically indicates that paternal smoking both before and during pregnancy contributes significantly to autism spectrum disorder risk. Implications for practice, research, or policy: Smoking prevention, especially in pregnancy planning, may decrease autism spectrum disorder risk in offspring.

Ketone body 3-hydroxybutyrate as a biomarker of aggression

Human aggression is a complex behaviour, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983–1987, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the response variable and aggression ratings as predictor variables, and included several potential confounders. All metabolites showed low correlations with aggression, with only one—3-hydroxybutyrate, a ketone body produced during fasting—showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated (age 14) aggression were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher aggression (self-rated) was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.

Twin Differences in Harsh Parenting Predict Youth’s Antisocial Behavior

In the current study, we leveraged differences within twin pairs to examine whether harsh parenting is associated with children’s antisocial behavior via environmental (vs. genetic) transmission. We examined two independent samples from the Michigan State University Twin Registry. Our primary sample contained 1,030 families (2,060 twin children; 49% female; 6–10 years old) oversampled for exposure to disadvantage. Our replication sample included 240 families (480 twin children; 50% female; 6–15 years old). Co-twin control analyses were conducted using a specification-curve framework, an exhaustive modeling approach in which all reasonable analytic specifications of the data are interrogated. Results revealed that, regardless of zygosity, the twin experiencing harsher parenting exhibited more antisocial behavior. These effects were robust across multiple operationalizations and informant reports of both harsh parenting and antisocial behavior with only a few exceptions. Results indicate that the association between harsh parenting and children’s antisocial behavior is, to a large degree, environmental in origin.