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The general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N = 2178 and N = 2190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p = 8.58 × 10–8). We also identified a significant differentially methylated region (DMR) at school-age (p = 1.63 × 10–8), implicating the SHC Adaptor Protein 4 (SHC4) gene and the EP300-interacting inhibitor of differentiation 1 (EID1) gene that have been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder, schizophrenia, and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.

Lower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.

Background Attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are child-onset neurodevelopmental disorders frequently accompanied by cognitive difficulties. In the current study, we aim to examine the genetic overlap between ADHD and ASD and cognitive measures of working memory (WM) and attention performance among schoolchildren using a polygenic risk approach. Methods A total of 1667 children from a population-based cohort aged 7-11 years with data available on genetics and cognition were included in the analyses. Polygenic risk scores (PRS) were calculated for ADHD and ASD using results from the largest GWAS to date (N = 55 374 and N = 46 351, respectively). The cognitive outcomes included verbal and numerical WM and the standard error of hit reaction time (HRTSE) as a measure of attention performance. These outcomes were repeatedly assessed over 1-year period using computerized version of the Attention Network Test and n-back task. Associations were estimated using linear mixed-effects models. Results Higher polygenic risk for ADHD was associated with lower WM performance at baseline time but not over time. These findings remained significant after adjusting by multiple testing and excluding individuals with an ADHD diagnosis but were limited to boys. PRS for ASD was only nominally associated with an increased improvement on verbal WM over time, although this association did not survive multiple testing correction. No associations were observed for HRTSE. Conclusions Common genetic variants related to ADHD may contribute to worse WM performance among schoolchildren from the general population but not to the subsequent cognitive-developmental trajectory assessed over 1-year period.

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way t

Autism spectrum disorders (ASD) are associated with widespread brain alterations. Previous research in our group linked autistic traits with altered gyrification, but without pronounced differences in cortical thickness. Herein, we aim to replicate and extend these findings using a larger and older sample. Additionally, we examined whether (a) brain correlates of autistic traits were associated with polygenic risk scores (PRS) for ASD, and (b) autistic traits are related with brain morphological changes over time in a subset of children with longitudinal data available. The sample included 2400 children from the Generation R cohort. Autistic traits were measured using the Social Responsiveness Scale (SRS) at age 6 years. Gyrification, cortical thickness, surface area, and global morphological measures were obtained from high-resolution structural MRI scans at ages 9-to-12 years. We performed multiple linear regression analyses on a vertex-wise level. Corresponding regions of interest were tested for association with PRS. Results showed that autistic traits were related to (a) lower gyrification in the lateral occipital and the superior and inferior parietal lobes, (b) lower cortical thickness in the superior frontal region, and (c) lower surface area in inferior temporal and rostral middle frontal regions. PRS for ASD and longitudinal analyses showed significant associations that did not survive correction for multiple testing. Our findings support stability in the relationship between higher autistic symptoms and lower gyrification and smaller surface areas in school-aged children. These relationships remained when excluding ASD cases, providing neurobiological evidence for the extension of autistic traits into the general population. Lay Summary: We found that school-aged children with higher levels of autistic traits had smaller total brain volume, cerebellum, cortical thickness, and surface area. Further, we also found differences in the folding patterns of t

Autism spectrum disorders (ASD) are associated with widespread brain alterations. Previous research in our group linked autistic traits with altered gyrification, but without pronounced differences in cortical thickness. Herein, we aim to replicate and extend these findings using a larger and older sample. Additionally, we examined whether (a) brain correlates of autistic traits were associated with polygenic risk scores (PRS) for ASD, and (b) autistic traits are related with brain morphological changes over time in a subset of children with longitudinal data available. The sample included 2400 children from the Generation R cohort. Autistic traits were measured using the Social Responsiveness Scale (SRS) at age 6 years. Gyrification, cortical thickness, surface area, and global morphological measures were obtained from high-resolution structural MRI scans at ages 9-to-12 years. We performed multiple linear regression analyses on a vertex-wise level. Corresponding regions of interest were tested for association with PRS. Results showed that autistic traits were related to (a) lower gyrification in the lateral occipital and the superior and inferior parietal lobes, (b) lower cortical thickness in the superior frontal region, and (c) lower surface area in inferior temporal and rostral middle frontal regions. PRS for ASD and longitudinal analyses showed significant associations that did not survive correction for multiple testing. Our findings support stability in the relationship between higher autistic symptoms and lower gyrification and smaller surface areas in school-aged children. These relationships remained when excluding ASD cases, providing neurobiological evidence for the extension of autistic traits into the general population. Lay Summary: We found that school-aged children with higher levels of autistic traits had smaller total brain volume, cerebellum, cortical thickness, and surface area. Further, we also found differences in the folding patterns of t

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.