Multivariate analyses of molecular genetic associations between childhood psychopathology and adult mood disorders and related traits.

Ubiquitous associations have been detected between different types of childhood psychopathology and polygenic risk scores based on adult psychiatric disorders and related adult outcomes, indicating that genetic factors partly explain the association between childhood psychopathology and adult outcomes. However, these analyses in general do not take into account the correlations between the adult trait and disorder polygenic risk scores. This study aimed to further clarify the influence of genetic factors on associations between childhood psychopathology and adult outcomes by accounting for these correlations. Using a multivariate multivariable regression, we analyzed associations of childhood attention-deficit/hyperactivity disorder (ADHD), internalizing, and social problems, with polygenic scores (PGS) of adult disorders and traits including major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI), derived for 20,539 children aged 8.5-10.5 years. After correcting for correlations between the adult phenotypes, major depression PGS were associated with all three childhood traits, that is, ADHD, internalizing, and social problems. In addition, BMI PGS were associated with ADHD symptoms and social problems, while neuroticism PGS were only associated with internalizing problems and educational attainment PGS were only associated with ADHD symptoms. PGS of bipolar disorder, subjective well-being, and insomnia were not associated with any childhood traits. Our findings suggest that associations between childhood psychopathology and adult traits like insomnia and subjective well-being may be primarily driven by genetic factors that influence adult major depression. Additionally, specific childhood phenotypes are genetically associated with educational attainment, BMI and neuroticism.

A genetically informed prediction model for suicidal and aggressive behaviour in teens.

Suicidal and aggressive behaviours cause significant personal and societal burden. As risk factors associated with these behaviours frequently overlap, combined approaches in predicting the behaviours may be useful in identifying those at risk for either. The current study aimed to create a model that predicted if individuals will exhibit suicidal behaviour, aggressive behaviour, both, or neither in late adolescence. A sample of 5,974 twins from the Child and Adolescent Twin Study in Sweden (CATSS) was broken down into a training (80%), tune (10%) and test (10%) set. The Netherlands Twin Register (NTR; N = 2702) was used for external validation. Our longitudinal data featured genetic, environmental, and psychosocial predictors derived from parental and self-report data. A stacked ensemble model was created which contained a gradient boosted machine, random forest, elastic net, and neural network. Model performance was transferable between CATSS and NTR (macro area under the receiver operating characteristic curve (AUC) [95% CI] AUCCATSS(test set) = 0.709 (0.671-0.747); AUCNTR = 0.685 (0.656-0.715), suggesting model generalisability across Northern Europe. The notable exception is suicidal behaviours in the NTR, which was no better than chance. The 25 highest scoring variable importance scores for the gradient boosted machines and random forest models included self-reported psychiatric symptoms in mid-adolescence, sex, and polygenic scores for psychiatric traits. The model's performance is comparable to current prediction models that use clinical interviews and is not yet suitable for clinical use. Moreover, genetic variables may have a role to play in predictive models of adolescent psychopathology.

Ultra-rare and common genetic variant analysis converge to implicate negative selection and neuronal processes in the aetiology of schizophrenia.

Both common and rare genetic variants (minor allele frequency >1% and <0.1% respectively) have been implicated in the aetiology of schizophrenia. In this study, we integrate single-cell gene expression data with publicly available Genome-Wide Association Study (GWAS) and exome sequenced data in order to investigate in parallel, the enrichment of common and (ultra-)rare variants related to schizophrenia in several functionally relevant gene-sets. Four types of gene-sets were constructed 1) protein-truncating variant (PTV)-intolerant (PI) genes 2) genes expressed in brain cell types and neurons ascertained from mouse and human brain tissue 3) genes defined by synaptic function and location and 4) intersection genes, i.e., PI genes that are expressed in the human and mouse brain cell gene-sets. We show that common as well as ultra-rare schizophrenia-associated variants are overrepresented in PI genes, in excitatory neurons from the prefrontal cortex and hippocampus, medium spiny neurons, and genes enriched for synaptic processes. We also observed stronger enrichment in the intersection genes. Our findings suggest that across the allele frequency spectrum, genes and genetic variants likely to be under stringent selection, and those expressed in particular brain cell types, are involved in the same biological pathways influencing the risk for schizophrenia.

Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis.

We interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. We identify four broad factors (neurodevelopmental, compulsive, psychotic and internalizing) that underlie genetic correlations among the disorders and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce stratified genomic structural equation modeling, which we use to identify gene sets that disproportionately contribute to genetic risk sharing. This includes protein-truncating variant-intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for genetic overlap across disorders with psychotic features. Multivariate association analyses detect 152 (20 new) independent loci that act on the individual factors and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate-to-high genetic correlations across all 11 disorders, we find little utility of a single dimension of genetic risk across psychiatric disorders either at the level of biobehavioral correlates or at the level of individual variants.

Overview of CAPICE-Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe-an EU Marie Sklodowska-Curie International Training Network.

The Roadmap for Mental Health and Wellbeing Research in Europe (ROAMER) identified child and adolescent mental illness as a priority area for research. CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) is a European Union (EU) funded training network aimed at investigating the causes of individual differences in common childhood and adolescent psychopathology, especially depression, anxiety, and attention deficit hyperactivity disorder. CAPICE brings together eight birth and childhood cohorts as well as other cohorts from the EArly Genetics and Life course Epidemiology (EAGLE) consortium, including twin cohorts, with unique longitudinal data on environmental exposures and mental health problems, and genetic data on participants. Here we describe the objectives, summarize the methodological approaches and initial results, and present the dissemination strategy of the CAPICE network. Besides identifying genetic and epigenetic variants associated with these phenotypes, analyses have been performed to shed light on the role of genetic factors and the interplay with the environment in influencing the persistence of symptoms across the lifespan. Data harmonization and building an advanced data catalogue are also part of the work plan. Findings will be disseminated to non-academic parties, in close collaboration with the Global Alliance of Mental Illness Advocacy Networks-Europe (GAMIAN-Europe).

Systematic Review: Molecular Studies of Common Genetic Variation in Child and Adolescent Psychiatric Disorders.

OBJECTIVE: A systematic review of studies using molecular genetics and statistical approaches to investigate the role of common genetic variation in the development, persistence, and comorbidity of childhood psychiatric traits was conducted. METHOD: A literature review was performed using the PubMed database, following PRISMA guidelines. There were 131 studies meeting inclusion criteria, having investigated at least one type of childhood-onset or childhood-measured psychiatric disorder or trait with the aim of identifying trait-associated common genetic variants, estimating the contribution of single nucleotide polymorphisms (SNPs) to the amount of variance explained (SNP-based heritability), investigating genetic overlap between psychiatric traits, or investigating whether the stability in traits or the association with adult traits is explained by genetic factors. RESULTS: The first robustly associated genetic variants have started to be identified for childhood psychiatric traits. There were substantial contributions of common genetic variants to many traits, with variation in single nucleotide polymorphism heritability estimates depending on age and raters. Moreover, genetic variants also appeared to explain comorbidity as well as stability across a range of psychiatric traits in childhood and across the life span. CONCLUSION: Common genetic variation plays a substantial role in childhood psychiatric traits. Increased sample sizes will lead to increased power to identify genetic variants and to understand genetic architecture, which will ultimately be beneficial to targeted and prevention strategies. This can be achieved by harmonizing phenotype measurements, as is already proposed by large international consortia and by including the collection of genetic material in every study.

Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42 998 Individuals: A Meta-analysis.

Importance: Adult mood disorders are often preceded by behavioral and emotional problems in childhood. It is yet unclear what explains the associations between childhood psychopathology and adult traits. Objective: To investigate whether genetic risk for adult mood disorders and associated traits is associated with childhood disorders. Design, Setting, and Participants: This meta-analysis examined data from 7 ongoing longitudinal birth and childhood cohorts from the UK, the Netherlands, Sweden, Norway, and Finland. Starting points of data collection ranged from July 1985 to April 2002. Participants were repeatedly assessed for childhood psychopathology from ages 6 to 17 years. Data analysis occurred from September 2017 to May 2019. Exposures: Individual polygenic scores (PGS) were constructed in children based on genome-wide association studies of adult major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI). Main Outcomes and Measures: Regression meta-analyses were used to test associations between PGS and attention-deficit/hyperactivity disorder (ADHD) symptoms and internalizing and social problems measured repeatedly across childhood and adolescence and whether these associations depended on childhood phenotype, age, and rater. Results: The sample included 42 998 participants aged 6 to 17 years. Male participants varied from 43.0% (1040 of 2417 participants) to 53.1% (2434 of 4583 participants) by age and across all cohorts. The PGS of adult major depression, neuroticism, BMI, and insomnia were positively associated with childhood psychopathology (ß estimate range, 0.023-0.042 [95% CI, 0.017-0.049]), while associations with PGS of subjective well-being and educational attainment were negative (ß, -0.026 to -0.046 [95% CI, -0.020 to -0.057]). There was no moderation of age, type of childhood phenotype, or rater with the associations. The exceptions were stronger associations between educational attainment PGS and ADHD compared with internalizing problems (Δß, 0.0561 [Δ95% CI, 0.0318-0.0804]; ΔSE, 0.0124) and social problems (Δß, 0.0528 [Δ95% CI, 0.0282-0.0775]; ΔSE, 0.0126), and between BMI PGS and ADHD and social problems (Δß, -0.0001 [Δ95% CI, -0.0102 to 0.0100]; ΔSE, 0.0052), compared with internalizing problems (Δß, -0.0310 [Δ95% CI, -0.0456 to -0.0164]; ΔSE, 0.0074). Furthermore, the association between educational attainment PGS and ADHD increased with age (Δß, -0.0032 [Δ 95% CI, -0.0048 to -0.0017]; ΔSE, 0.0008). Conclusions and Relevance: Results from this study suggest the existence of a set of genetic factors influencing a range of traits across the life span with stable associations present throughout childhood. Knowledge of underlying mechanisms may affect treatment and long-term outcomes of individuals with psychopathology.