Genetic effects on variability in visual aesthetic evaluations are partially shared across visual domains.

The aesthetic values that individuals place on visual images are formed and shaped over a lifetime. However, whether the formation of visual aesthetic value is solely influenced by environmental exposure is still a matter of debate. Here, we considered differences in aesthetic value emerging across three visual domains: abstract images, scenes, and faces. We examined variability in two major dimensions of ordinary aesthetic experiences: taste-typicality and evaluation-bias. We build on two samples from the Australian Twin Registry where 1547 and 1231 monozygotic and dizygotic twins originally rated visual images belonging to the three domains. Genetic influences explained 26% to 41% of the variance in taste-typicality and evaluation-bias. Multivariate analyses showed that genetic effects were partially shared across visual domains. Results indicate that the heritability of major dimensions of aesthetic evaluations is comparable to that of other complex social traits, albeit lower than for other complex cognitive traits. The exception was taste-typicality for abstract images, for which we found only shared and unique environmental influences. Our study reveals that diverse sources of genetic and environmental variation influence the formation of aesthetic value across distinct visual domains and provides improved metrics to assess inter-individual differences in aesthetic value.

The effects of COVID-19 on child mental health: Biannual assessments up to April 2022 in a clinical and two general population samples.

Background: The COVID-19 pandemic has had an acute impact on child mental and social health, but long-term effects are still unclear. We examined how child mental health has developed since the start of the COVID-19 pandemic up to 2 years into the pandemic (April 2022). Methods: We included children (age 8-18) from two general population samples (N = 222-1333 per measurement and N = 2401-13,362 for pre-covid data) and one clinical sample receiving psychiatric care (N = 334-748). Behavioral questionnaire data were assessed five times from April 2020 till April 2022 and pre-pandemic data were available for both general population samples. We collected parent-reported data on internalizing and externalizing problems with the Brief Problem Monitor and self-reported data on Anxiety, Depressive symptoms, Sleep-related impairments, Anger, Global health, and Peer relations with the Patient-Reported Outcomes Measurement Information System (PROMIS®). Results: In all samples, parents reported overall increased internalizing problems, but no increases in externalizing problems, in their children. Children from the general population self-reported increased mental health problems from before to during the pandemic on all six PROMIS domains, with generally worst scores in April 2021, and scores improving toward April 2022 but not to pre-pandemic norms. Children from the clinical sample reported increased mental health problems throughout the pandemic, with generally worst scores in April 2021 or April 2022 and no improvement. We found evidence of minor age effects and no sex effects. Conclusions: Child mental health in the general population has deteriorated during the first phase of the COVID-19 pandemic, has improved since April 2021, but has not yet returned to pre-pandemic levels. Children in psychiatric care show worsening of mental health problems during the pandemic, which has not improved since. Changes in child mental health should be monitored comprehensively to inform health care and policy.

Internalizing problems before and during the COVID-19 pandemic in independent samples of Dutch children and adolescents with and without pre-existing mental health problems.

The aim of the study was to assess internalizing problems before and during the pandemic with data from Dutch consortium Child and adolescent mental health and wellbeing in times of the COVID-19 pandemic, consisting of two Dutch general population samples (GS) and two clinical samples (CS) referred to youth/psychiatric care. Measures of internalizing problems were obtained from ongoing data collections pre-pandemic (NGS = 35,357; NCS = 4487) and twice during the pandemic, in Apr-May 2020 (NGS = 3938; clinical: NCS = 1008) and in Nov-Dec 2020 (NGS = 1489; NCS = 1536), in children and adolescents (8-18 years) with parent (Brief Problem Monitor) and/or child reports (Patient-Reported Outcomes Measurement Information System®). Results show that, in the general population, internalizing problems were higher during the first peak of the pandemic compared to pre-pandemic based on both child and parent reports. Yet, over the course of the pandemic, on both child and parent reports, similar or lower levels of internalizing problems were observed. Children in the clinical population reported more internalizing symptoms over the course of the pandemic while parents did not report differences in internalizing symptoms from pre-pandemic to the first peak of the pandemic nor over the course of the pandemic. Overall, the findings indicate that children and adolescents of both the general and clinical population were affected negatively by the pandemic in terms of their internalizing problems. Attention is therefore warranted to investigate long-term effects and to monitor if internalizing problems return to pre-pandemic levels or if they remain elevated post-pandemic.

Mental and Social Health of Children and Adolescents With Pre-existing Mental or Somatic Problems During the COVID-19 Pandemic Lockdown.

Background: The COVID-19 lockdown increases psychological problems in children and adolescents from the general population. Here we investigate the mental and social health during the COVID-19 lockdown in children and adolescents with pre-existing mental or somatic problems. Methods: We included participants (8-18 years) from a psychiatric (N = 249) and pediatric (N = 90) sample, and compared them to a general population sample (N = 844). Measures were assessed during the first lockdown (April-May 2020) in the Netherlands. Main outcome measures were Patient-Reported Outcomes Measurement Information System (PROMIS®) domains: Global Health, Peer Relationships, Anxiety, Depressive Symptoms, Anger, and Sleep-Related Impairment, as reported by children and youth. Additionally, socio-demographic variables, COVID-19-related questions, changes in atmosphere at home from a parent and child perspective, and children's experiences of lockdown regulations were reported by parents. Results: On all measures except Global Health, the pediatric sample reported least problems. The psychiatric sample reported significantly more problems than the general population sample on all measures except for Anxiety and Peer Relationships. Having a COVID-19 affected friend/relative and a COVID-19 related change in parental work situation negatively moderated outcome, but not in the samples with pre-existing problems. All parents reported significant decreases in atmosphere at home, as did children from the general population. Conclusion: We observed significant differences in mental and social health between three child and adolescent samples during the COVID-19 pandemic lockdown and identified COVID-19-related factors influencing mental and social health.

The impact of lockdown during the COVID-19 pandemic on mental and social health of children and adolescents.

PURPOSE: During the COVID-19 pandemic in the Netherlands, governmental regulations resulted in a lockdown for adults as well as children/adolescents. Schools were closed and contact with other people was limited. In this cross-sectional, population-based study, we aimed to investigate the mental/social health of children/adolescents during COVID-19 lockdown. METHODS: Two representative samples of Dutch children/adolescents (8-18 years) before COVID-19 (2018, N = 2401) and during lockdown (April 2020, N = 844) were compared on the Patient-Reported Outcomes Measurement Information System (PROMIS) domains: global health, peer relationships, anxiety, depressive symptoms, anger, sleep-related impairment by linear mixed models and calculating relative risks (RR (95% CI)) for the proportion of severe scores. Variables associated with worse mental/social health during COVID-19 were explored through multivariable regression models. The impact of COVID-19 regulations on the daily life of children was qualitatively analyzed. RESULTS: Participants reported worse PROMIS T-scores on all domains during COVID-19 lockdown compared to before (absolute mean difference range 2.1-7.1 (95% CI 1.3-7.9). During lockdown, more children reported severe Anxiety (RR = 1.95 (1.55-2.46) and Sleep-Related Impairment (RR = 1.89 (1.29-2.78) and fewer children reported poor Global Health (RR = 0.36 (0.20-0.65)). Associated factors with worse mental/social health were single-parent family, ≥ three children in the family, negative change in work situation of parents due to COVID-19 regulations, and a relative/friend infected with COVID-19. A large majority (> 90%) reported a negative impact of the COVID-19 regulations on daily life. CONCLUSION: This study showed that governmental regulations regarding lockdown pose a serious mental/social health threat on children/adolescents that should be brought to the forefront of political decision-making and mental healthcare policy, intervention, and prevention.

The predictive capacity of psychiatric and psychological polygenic risk scores for distinguishing cases in a child and adolescent psychiatric sample from controls.

BACKGROUND: Psychiatric traits are heritable, highly comorbid and genetically correlated, suggesting that genetic effects that are shared across disorders are at play. The aim of the present study is to quantify the predictive capacity of common genetic variation of a variety of traits, as captured by their PRS, to predict case-control status in a child and adolescent psychiatric sample including controls to reveal which traits contribute to the shared genetic risk across disorders. METHOD: Polygenic risk scores (PRS) of 14 traits were used as predictor phenotypes to predict case-control status in a clinical sample. Clinical cases (N = 1,402), age 1-21, diagnostic categories: Autism spectrum disorders (N = 492), Attention-deficit/ hyperactivity disorders (N = 471), Anxiety (N = 293), disruptive behaviors (N = 101), eating disorders (N = 97), OCD (N = 43), Tic disorder (N = 50), Disorder of infancy, childhood or adolescence NOS (N = 65), depression (N = 64), motor, learning and communication disorders (N = 59), Anorexia Nervosa (N = 48), somatoform disorders (N = 47), Trauma/stress (N = 39) and controls (N = 1,448, age 17-84) of European ancestry. First, these 14 PRS were tested in univariate regression analyses. The traits that significantly predicted case-control status were included in a multivariable regression model to investigate the gain in explained variance when leveraging the genetic effects of multiple traits simultaneously. RESULTS: In the univariate analyses, we observed significant associations between clinical status and the PRS of educational attainment (EA), smoking initiation (SI), intelligence, neuroticism, alcohol dependence, ADHD, major depression and anti-social behavior. EA (p-value: 3.53E-20, explained variance: 3.99%, OR: 0.66), and SI (p-value: 4.77E-10, explained variance: 1.91%, OR: 1.33) were the most predictive traits. In the multivariable analysis with these eight significant traits, EA and SI, remained significant predictors. The explained variance of the PRS in the model with these eight traits combined was 5.9%. CONCLUSION: Our study provides more insights into the genetic signal that is shared between childhood and adolescent psychiatric disorders. As such, our findings might guide future studies on psychiatric comorbidity and offer insights into shared etiology between psychiatric disorders. The increase in explained variance when leveraging the genetic signal of different predictor traits supports a multivariable approach to optimize precision accuracy for general psychopathology.

Systematic Review: How the Attention-Deficit/Hyperactivity Disorder Polygenic Risk Score Adds to Our Understanding of ADHD and Associated Traits.

OBJECTIVE: To investigate, by systematically reviewing the literature, whether the attention-deficit/hyperactivity disorder (ADHD) polygenic risk score (PRS) associates with ADHD and related traits in independent clinical and population samples. METHOD: PubMed, Embase and PsychoInfo were systematically searched, alongside study bibliographies. Quality assessments were conducted, and a best-evidence synthesis was applied. Studies were excluded when the predictor was not based on the latest ADHD genome-wide association study, when PRS was not based on genome-wide results, or when the study was a review. Initially, 197 studies were retrieved (February 22, 2020), and a second search (June 3, 2020) yielded a further 49 studies. From both searches, 57 studies were eligible, and 44 studies met inclusion criteria. RESULTS: Included studies were published in the last 3 years. Over 80% of the studies were rated excellent, based on a standardized quality assessment. Evidence of associations between ADHD PRS and the following categories was strong: ADHD, ADHD traits, brain structure, education, externalizing behaviors, neuropsychological constructs, physical health, and socioeconomic status. Evidence for associations with addiction, autism, and mental health were mixed and were, so far, inconclusive. Odds ratios for PRS associating with ADHD ranged from 1.22% to 1.76%; variance explained in dimensional assessments of ADHD traits was 0.7% to 3.3%. CONCLUSION: A new wave of high-quality research using the ADHD PRS has emerged. Eventually, symptoms may be partly identified based on PRS, but the current ADHD PRS is useful for research purposes only. This review shows that the ADHD PRS is robust and reliable, associating not only with ADHD but many outcomes and challenges known to be linked to ADHD.

Author Correction: A global overview of pleiotropy and genetic architecture in complex traits.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Psychiatric Polygenic Risk Scores as Predictor for Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in a Clinical Child and Adolescent Sample.

Neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable and influenced by many single nucleotide polymorphisms (SNPs). SNPs can be used to calculate individual polygenic risk scores (PRS) for a disorder. We aim to explore the association between the PRS for ADHD, ASD and for Schizophrenia (SCZ), and ADHD and ASD diagnoses in a clinical child and adolescent population. Based on the most recent genome wide association studies of ADHD, ASD and SCZ, PRS of each disorder were calculated for individuals of a clinical child and adolescent target sample (N = 688) and for adult controls (N = 943). We tested with logistic regression analyses for an association with (1) a single diagnosis of ADHD (N = 280), (2) a single diagnosis of ASD (N = 295), and (3) combining the two diagnoses, thus subjects with either ASD, ADHD or both (N = 688). Our results showed a significant association of the ADHD PRS with ADHD status (OR 1.6, P = 1.39 × 10-07) and with the combined ADHD/ASD status (OR 1.36, P = 1.211 × 10-05), but not with ASD status (OR 1.14, P = 1). No associations for the ASD and SCZ PRS were observed. In sum, the PRS of ADHD is significantly associated with the combined ADHD/ASD status. Yet, this association is primarily driven by ADHD status, suggesting disorder specific genetic effects of the ADHD PRS.

Editorial: The Genetic Overlap Between Cognitive Abilities and a Transdiagnostic Vulnerability for Psychopathology.

Cognitive abilities, such as working memory, selective attention, inhibition, alertness, and flexibility, are collectively known as executive functioning (EF), which is essential in daily life routines. For instance, EF is important when planning a series of actions, in novel situations, or during the performance of complex tasks. General intelligence, or g, is a related construct and involves, for instance, the ability to reason, plan, solve problems, think abstractly, and learn from experience. The concept g is usually measured with a psychometric intelligence test. It has been known for more than a decade that EF and, in particular, g are negatively correlated with psychopathology. Yet, the underlying source of this correlation is largely unknown.

Synaptic and brain-expressed gene sets relate to the shared genetic risk across five psychiatric disorders.

BACKGROUND: Mounting evidence shows genetic overlap between multiple psychiatric disorders. However, the biological underpinnings of shared risk for psychiatric disorders are not yet fully uncovered. The identification of underlying biological mechanisms is crucial for the progress in the treatment of these disorders. METHODS: We applied gene-set analysis including 7372 gene sets, and 53 tissue-type specific gene-expression profiles to identify sets of genes that are involved in the etiology of multiple psychiatric disorders. We included genome-wide meta-association data of the five psychiatric disorders schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. The total dataset contained 159 219 cases and 262 481 controls. RESULTS: We identified 19 gene sets that were significantly associated with the five psychiatric disorders combined, of which we excluded five sets because their associations were likely driven by schizophrenia only. Conditional analyses showed independent effects of several gene sets that in particular relate to the synapse. In addition, we found independent effects of gene expression levels in the cerebellum and frontal cortex. CONCLUSIONS: We obtained novel evidence for shared biological mechanisms that act across psychiatric disorders and we showed that several gene sets that have been related to individual disorders play a role in a broader range of psychiatric disorders.

A global overview of pleiotropy and genetic architecture in complex traits.

After a decade of genome-wide association studies (GWASs), fundamental questions in human genetics, such as the extent of pleiotropy across the genome and variation in genetic architecture across traits, are still unanswered. The current availability of hundreds of GWASs provides a unique opportunity to address these questions. We systematically analyzed 4,155 publicly available GWASs. For a subset of well-powered GWASs on 558 traits, we provide an extensive overview of pleiotropy and genetic architecture. We show that trait-associated loci cover more than half of the genome, and 90% of these overlap with loci from multiple traits. We find that potential causal variants are enriched in coding and flanking regions, as well as in regulatory elements, and show variation in polygenicity and discoverability of traits. Our results provide insights into how genetic variation contributes to trait variation. All GWAS results can be queried and visualized at the GWAS ATLAS resource ( https://atlas.ctglab.nl ).

Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways.

Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited. Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.

Common Polygenic Variations for Psychiatric Disorders and Cognition in Relation to Brain Morphology in the General Pediatric Population.

OBJECTIVE: This study examined the relation between polygenic scores (PGSs) for 5 major psychiatric disorders and 2 cognitive traits with brain magnetic resonance imaging morphologic measurements in a large population-based sample of children. In addition, this study tested for differences in brain morphology-mediated associations between PGSs for psychiatric disorders and PGSs for related behavioral phenotypes. METHOD: Participants included 1,139 children from the Generation R Study assessed at 10 years of age with genotype and neuroimaging data available. PGSs were calculated for schizophrenia, bipolar disorder, major depression disorder, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, intelligence, and educational attainment using results from the most recent genome-wide association studies. Image processing was performed using FreeSurfer to extract cortical and subcortical brain volumes. RESULTS: Greater genetic susceptibility for ADHD was associated with smaller caudate volume (strongest prior = 0.01: ß = -0.07, p = .006). In boys, mediation analysis estimates showed that 11% of the association between the PGS for ADHD and the PGS attention problems was mediated by differences in caudate volume (n = 535), whereas mediation was not significant in girls or the entire sample. PGSs for educational attainment and intelligence showed positive associations with total brain volume (strongest prior = 0.5: ß = 0.14, p = 7.12 × 10-8; and ß = 0.12, p = 6.87 × 10-7, respectively). CONCLUSION: The present findings indicate that the neurobiological manifestation of polygenic susceptibility for ADHD, educational attainment, and intelligence involve early morphologic differences in caudate and total brain volumes in childhood. Furthermore, the genetic risk for ADHD might influence attention problems through the caudate nucleus in boys.

Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use.

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

Polygenic Scores for Neuropsychiatric Traits and White Matter Microstructure in the Pediatric Population.

BACKGROUND: Genome-wide association studies have identified numerous genetic variants that predispose to neuropsychiatric traits. Identification of mechanisms in the brain that underlie these associations is essential for understanding manifestations of genetic predisposition within the general population. Here, we investigated the association between polygenic scores (PGSs) for seven neuropsychiatric traits and white matter microstructure of the brain on diffusion tensor imaging in the pediatric population. METHODS: Participants from the Generation R Study who had genotype and diffusion tensor imaging data available (n = 1138, mean age = 10.2 years, range = 8.7-12.0) were included. PGSs were calculated for five psychiatric disorders (attention-deficit/hyperactivity disorder, bipolar disorder, autism, major depressive disorder, and schizophrenia) and two cognitive traits (intelligence and educational attainment) and were tested for associations with global and tract-specific fractional anisotropy (FA) and mean diffusivity. RESULTS: Significant positive associations with global FA were observed for the PGSs of intelligence (ß = .109, SE = .029, p < .001, ΔR2 = .012) and educational attainment (ß = .118, SE = .029, p < .001, ΔR2 = .014). No significant associations were observed with FA for the PGSs of psychiatric disorders. Tract-specific analysis showed that the PGSs for intelligence and educational attainment were associated with FA of several association and projection fibers of the brain. CONCLUSIONS: Our results show that genetic predisposition for cognition-related traits, but not for psychiatric disorders, is associated with microstructural diffusion measures of white matter tracts at an early age. These results suggest a shared genetic etiology among structural connectivity, intelligence, and educational achievement.

Author Correction: Majority of human traits do not show evidence for sex-specific genetic and environmental effects.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Exploring the genetic correlations of antisocial behaviour and life history traits.

Prior evolutionary theory provided reason to suspect that measures of development and reproduction would be correlated with antisocial behaviours in human and non-human species. Behavioural genetics has revealed that most quantitative traits are heritable, suggesting that these phenotypic correlations may share genetic aetiologies. We use genome-wide association study data to estimate the genetic correlations between various measures of reproductive development (N = 52 776-318 863) and antisocial behaviour (N = 31 968). Our genetic correlation analyses demonstrate that alleles associated with higher reproductive output (number of children ever born, r g = 0.50, P = 0.0065) were positively correlated with alleles associated with antisocial behaviour, whereas alleles associated with more delayed reproductive onset (age at first birth, r g = -0.64, P = 0.0008) were negatively associated with alleles linked to antisocial behaviour. Ultimately, these findings coalesce with evolutionary theories suggesting that increased antisocial behaviours may partly represent a faster life history approach, which may be significantly calibrated by genes. DECLARATION OF INTEREST: None.