Integrative multi-omics analysis of genomic, epigenomic, and metabolomics data leads to new insights for Attention-Deficit/Hyperactivity Disorder.

The evolving field of multi-omics combines data and provides methods for simultaneous analysis across several omics levels. Here, we integrated genomics (transmitted and non-transmitted polygenic scores [PGSs]), epigenomics, and metabolomics data in a multi-omics framework to identify biomarkers for Attention-Deficit/Hyperactivity Disorder (ADHD) and investigated the connections among the three omics levels. We first trained single- and next multi-omics models to differentiate between cases and controls in 596 twins (cases = 14.8%) from the Netherlands Twin Register (NTR) demonstrating reasonable in-sample prediction through cross-validation. The multi-omics model selected 30 PGSs, 143 CpGs, and 90 metabolites. We confirmed previous associations of ADHD with glucocorticoid exposure and the transmembrane protein family TMEM, show that the DNA methylation of the MAD1L1 gene associated with ADHD has a relation with parental smoking behavior, and present novel findings including associations between indirect genetic effects and CpGs of the STAP2 gene. However, out-of-sample prediction in NTR participants (N = 258, cases = 14.3%) and in a clinical sample (N = 145, cases = 51%) did not perform well (range misclassification was [0.40, 0.57]). The results highlighted connections between omics levels, with the strongest connections between non-transmitted PGSs, CpGs, and amino acid levels and show that multi-omics designs considering interrelated omics levels can help unravel the complex biology underlying ADHD.

Psychopathic Traits and Parental Practices in Greek-Cypriot Community and Dutch Clinical Referred Samples.

Parental practices are associated with psychopathic traits across several developmental stages. However, the majority of available studies focused mainly on the affective dimension of psychopathy, namely callous-unemotional traits, disregarding the grandiose-deceitful and impulsivity-need for stimulation dimensions. The current study examines the distinct associations between all three dimensions with parental practices (parental involvement, poor monitoring, inconsistent discipline, and corporal punishment) after considering the effect of conduct problems (CPs) and sex in a Greek-Cypriot primary school sample (N = 792, Mage = 6.93, SD = 0.72) and a Dutch clinical-referred sample (N = 217, Mage = 9.55, SD = 1.79) of children. In the community sample, hierarchical multiple regression analysis revealed that parents of children with high levels of callous-unemotional traits were more likely to engage in inconsistent discipline but less in positive parental practices. In contrast, high levels of impulsivity-need for stimulation were related to inconsistent discipline. In the clinical sample, callous-unemotional traits were associated with less parental involvement and grandiose-deceitful dimension with high levels of inconsistent discipline. These findings suggest that the three psychopathy dimensions have unique relations with parental practices above and beyond CPs, proposing that parental practices may be influenced more strongly by psychopathic traits than by antisocial behavior.

Integrative Multi-omics Analysis of Childhood Aggressive Behavior.

This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.

Heritability of Urinary Amines, Organic Acids, and Steroid Hormones in Children.

Variation in metabolite levels reflects individual differences in genetic and environmental factors. Here, we investigated the role of these factors in urinary metabolomics data in children. We examined the effects of sex and age on 86 metabolites, as measured on three metabolomics platforms that target amines, organic acids, and steroid hormones. Next, we estimated their heritability in a twin cohort of 1300 twins (age range: 5.7-12.9 years). We observed associations between age and 50 metabolites and between sex and 21 metabolites. The monozygotic (MZ) and dizygotic (DZ) correlations for the urinary metabolites indicated a role for non-additive genetic factors for 50 amines, 13 organic acids, and 6 steroids. The average broad-sense heritability for these amines, organic acids, and steroids was 0.49 (range: 0.25-0.64), 0.50 (range: 0.33-0.62), and 0.64 (range: 0.43-0.81), respectively. For 6 amines, 7 organic acids, and 4 steroids the twin correlations indicated a role for shared environmental factors and the average narrow-sense heritability was 0.50 (range: 0.37-0.68), 0.50 (range; 0.23-0.61), and 0.47 (range: 0.32-0.70) for these amines, organic acids, and steroids. We conclude that urinary metabolites in children have substantial heritability, with similar estimates for amines and organic acids, and higher estimates for steroid hormones.

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Classes of Oppositional Defiant Disorder Behavior in Clinic-referred Children and Adolescents: Concurrent Features and Outcomes: Classification Des Comportements Dans le Trouble Oppositionnel Avec Provocation Chez Des Enfants et des Adolescents Aiguillés à Une Clinique: Caractéristiques Co-occurrentes et Résultats.

OBJECTIVE: Oppositional defiant disorder (ODD) consists of irritable and oppositional behaviors, both of which are associated with different problems. However, it is unclear whether irritability and oppositionality enable classification of clinic-referred children and adolescents into mutually exclusive groups (e.g., high in oppositionality, low in irritability), and whether this classification is clinically meaningful. METHOD: As part of a clinical protocol, ODD behaviors were assessed at referral through a comprehensive diagnostic interview and questionnaire. Parent- and teacher-reported ODD of 2,185 clinic-referred 5- to 18-year-olds (36.9% females) were used in latent class analysis. Resulting ODD classes were compared, concurrently at referral, and, longitudinally at the end of the diagnostic and treatment process, on various clinically relevant measures that were completed by various informants, including mental health problems, global functioning, and Diagnostic and Statistical Manual of Mental Disorders (DSM) classifications. RESULTS: Three classes emerged with high, moderate, and low levels of both irritability and oppositionality. At referral, the high class experienced the highest levels of mental health problems and DSM classifications. Importantly, all ODD classes defined at intake were predictive of diagnostic and treatment outcomes months later. Notably, the high class had higher rates of clinician-based classifications of ODD and conduct disorder, and the lowest levels of pre- and posttreatment global functioning. Additionally, the low class exhibited higher rates of generalized anxiety disorder and fear disorders. CONCLUSIONS: Irritability and oppositionality co-occur in clinic-referred youths to such an extent that classification based on these behaviors does not add to clinical inference. Instead, findings suggest that the overall ODD severity at referral should be used as a guidance for treatment.

Correction: What Do Parents Expect in the 21st Century? A Qualitative Analysis of Integrated Youth Care.

[This corrects the article DOI: 10.5334/ijic.5419.].

What Do Parents Expect in the 21st Century? A Qualitative Analysis of Integrated Youth Care.

INTRODUCTION: To provide integrated Youth Care responsive to the needs of families with multiple problems across life domains, it is essential to incorporate parental perspectives into clinical practice. The aim of this study is to advance our understanding of key components of integrated Youth Care from a parental perspective. METHODS: Semi-structured interviews were administered to 21 parents of children receiving Youth Care from integrated care teams in the Netherlands. Qualitative content analysis was conducted by means of a grounded theory approach following qualitative reporting guidelines. RESULTS AND DISCUSSION: Parental perspectives were clustered into six key components: a holistic, family-centred approach; addressing a broad range of needs in a timely manner; shared decision making; interprofessional collaboration; referral; and privacy. Parents emphasized the importance of a tailored, family-centred approach, addressing needs across several life domains, and active participation in their own care process. However, they simultaneously had somewhat opposing expectations regarding these key components, for example, concerning the changing roles of professionals and parents in shared decision making and the value of involving family members in a care process. Professionals should be aware of these opposing expectations by explicitly discussing mutual expectations and changing roles in decision making during a care process. To enable parents to make their own decisions, professionals should transparently propose different options for support guided by an up-to-date care plan.

Urinary Amine and Organic Acid Metabolites Evaluated as Markers for Childhood Aggression: The ACTION Biomarker Study.

Biomarkers are of interest as potential diagnostic and predictive instruments in personalized medicine. We present the first urinary metabolomics biomarker study of childhood aggression. We aim to examine the association of urinary metabolites and neurotransmitter ratios involved in key metabolic and neurotransmitter pathways in a large cohort of twins (N = 1,347) and clinic-referred children (N = 183) with an average age of 9.7 years. This study is part of ACTION (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies), in which we developed a standardized protocol for large-scale collection of urine samples in children. Our analytical design consisted of three phases: a discovery phase in twins scoring low or high on aggression (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (ß = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine (ß = 0.32; SE = 0.09; p = 0.01) remained significant after multiple testing. Although non-significant, the directions of effect were congruent between the discovery and replication analyses for six biomarkers and two neurotransmitter ratios and the concentrations of 6 amines differed between low and high aggressive twins. In the validation analyses, the top biomarkers and neurotransmitter ratios, with congruent directions of effect, showed no significant associations with childhood aggression. We find suggestive evidence for associations of childhood aggression with metabolic dysregulation of neurotransmission, oxidative stress, and energy metabolism. Although replication is required, our findings provide starting points to investigate causal and pleiotropic effects of these dysregulations on childhood aggression.

Assessing Psychopathic Traits Among Children: The First Validation Study of the Child Problematic Traits Inventory in a Clinical Sample.

This is the first study that tested the psychometric properties of the Child Problematic Traits Inventory (CPTI) in clinic-referred children (ages 6-13 years). Teachers (N = 159) and parents (N = 173) completed the CPTI and various other measures. Confirmatory factor analyses supported the CPTI's three-factor structure when teachers and parents rated the 28 CPTI items. Teacher- and parent-reported CPTI scores showed the expected relations with external correlates (e.g., conduct problems and proactive aggression). Crucially, the validity of the CPTI scores was also supported across informants (i.e., when linking teacher-reported CPTI scores to parent-reported external correlates, and vice versa) and across methods (i.e., regardless if a questionnaire or a diagnostic interview was used to measure external correlates). We conclude that the CPTI holds promise as a research tool for assessing psychopathic traits in clinic-referred children. Until our findings have been replicated and extended, the CPTI should not be used for clinical decision making.

Genomics of human aggression: current state of genome-wide studies and an automated systematic review tool.

There are substantial differences, or variation, between humans in aggression, with its molecular genetic basis mostly unknown. This review summarizes knowledge on the genetic contribution to variation in aggression with the following three foci: (1) a comprehensive overview of reviews on the genetics of human aggression, (2) a systematic review of genome-wide association studies (GWASs), and (3) an automated tool for the selection of literature based on supervised machine learning. The phenotype definition 'aggression' (or 'aggressive behaviour', or 'aggression-related traits') included anger, antisocial behaviour, conduct disorder, and oppositional defiant disorder. The literature search was performed in multiple databases, manually and using a novel automated selection tool, resulting in 18 reviews and 17 GWASs of aggression. Heritability estimates of aggression in children and adults are around 50%, with relatively small fluctuations around this estimate. In 17 GWASs, 817 variants were reported as suggestive (P ≤ 1.0E), including 10 significant associations (P ≤ 5.0E). Nominal associations (P ≤ 1E) were found in gene-based tests for genes involved in immune, endocrine, and nervous systems. Associations were not replicated across GWASs. A complete list of variants and their position in genes and chromosomes are available online. The automated literature search tool produced literature not found by regular search strategies. Aggression in humans is heritable, but its genetic basis remains to be uncovered. No sufficiently large GWASs have been carried out yet. With increases in sample size, we expect aggression to behave like other complex human traits for which GWAS has been successful.