Co-occurrence of mental disorders is commonly observed, but the etiology underlying this observation is poorly understood. Studies in adolescents and adults have identified a general psychopathology ...factor associated with a high risk for different psychiatric disorders. We defined a multi-informant general psychopathology factor in school-aged children and estimated its single nucleotide polymorphism (SNP) heritability. The goal was to test the hypothesis that child behavioral and emotional problems are under the influence of highly pleiotropic common autosomal genetic variants that nonspecifically increase the risk for different dimensions of psychopathology.
Children from the Generation R cohort were repeatedly assessed between ages 6 to 8 years. Child behavior problems were reported by parents, teachers, and children. Confirmatory factor analysis estimated a general psychopathology factor across informants using various psychiatric problem scales. Validation of the general psychopathology factor was based on IQ and temperamental measures. Genome-wide complex trait analysis (GCTA) was used to estimate the SNP heritability (N = 2,115).
The general psychopathology factor was associated with lower IQ, higher negative affectivity, and lower effortful control, but not with surgency. Importantly, the general psychopathology factor showed a significant SNP heritability of 38% (SE = 0.16, p = .008).
Common autosomal SNPs are pleiotropically associated with internalizing, externalizing, and other child behavior problems, and underlie a general psychopathology factor in childhood.
Preschool internalizing problems (INT) are highly heritable and moderately genetically stable from childhood into adulthood. Gene-finding studies are scarce. In this study, the influence of ...genome-wide measured single nucleotide polymorphisms (SNPs) was investigated in 3 cohorts (total N = 4,596 children) in which INT was assessed with the same instrument, the Child Behavior Checklist (CBCL).
First, genome-wide association (GWA) results were used for density estimation and genome-wide complex trait analysis (GCTA) to calculate the variance explained by all SNPs. Next, a fixed-effect inverse variance meta-analysis of the 3 GWA analyses was carried out. Finally, the overlap in results with prior GWA studies of childhood and adulthood psychiatric disorders and treatment responses was tested by examining whether SNPs associated with these traits jointly showed a significant signal for INT.
Genome-wide SNPs explained 13% to 43% of the total variance. This indicates that the genetic architecture of INT mirrors the polygenic model underlying adult psychiatric traits. The meta-analysis did not yield a genome-wide significant signal but was suggestive for the PCSK2 gene located on chromosome 20p12.1. SNPs associated with other psychiatric disorders appeared to be enriched for signals with INT (λ = 1.26, p < .03).
Our study provides evidence that INT is influenced by many common genetic variants, each with a very small effect, and that, even as early as age 3, genetic variants influencing INT overlap with variants that play a role in childhood and adulthood psychiatric disorders.
Reactive and proactive subtypes of aggression have been recognized to help parse etiological heterogeneity of this complex phenotype. With a heritability of about 50%, genetic factors play a role in ...the development of aggressive behavior. Imaging studies implicate brain structures related to social behavior in aggression etiology, most notably the amygdala and striatum. This study aimed to gain more insight into the pathways from genetic risk factors for aggression to aggression phenotypes. To this end, we conducted genome-wide gene-based cross-trait meta-analyses of aggression with the volumes of amygdala, nucleus accumbens and caudate nucleus to identify genes influencing both aggression and aggression-related brain volumes. We used data of large-scale genome-wide association studies (GWAS) of: (a) aggressive behavior in children and adolescents (EAGLE,
= 18,988); and (b) Magnetic Resonance Imaging (MRI)-based volume measures of aggression-relevant subcortical brain regions (ENIGMA2,
= 13,171). Second, the identified genes were further investigated in a sample of healthy adults (mean age (SD) = 25.28 (4.62) years; 43% male) who had genome-wide genotyping data and questionnaire data on aggression subtypes available (Brain Imaging Genetics, BIG,
= 501) to study their effect on reactive and proactive subtypes of aggression. Our meta-analysis identified two genes,
and
, significantly associated with both aggression risk and nucleus accumbens
and amygdala
brain volume. Subsequent in-depth analysis of these genes in healthy adults (BIG), including sex as an interaction term in the model, revealed no significant subtype-specific gene-wide associations. Using cross-trait meta-analysis of brain measures and psychiatric phenotypes, this study generated new hypotheses about specific links between genes, the brain and behavior. Results indicate that
and
may exert an effect on aggression through mechanisms involving nucleus accumbens and amygdala volumes, respectively.
Genetic factors contribute to individual differences in behavior problems. In children, genome-wide association studies (GWAS) have yielded the first suggestive results when aiming to identify ...genetic variants that explain heritability, but the proportion of genetic variance that can be attributed to common single nucleotide polymorphisms (SNPs) remains to be determined, as only a few studies have estimated SNP heritability, with diverging results.
Genomic-relationship-matrix restricted maximum likelihood (GREML) as implemented in the software Genome-Wide Complex Trait Analysis (GCTA) was used to estimate SNP heritability (SNP h(2)) for multiple phenotypes within 4 broad domains of children's behavioral problems (attention-deficit/hyperactivity symptoms, internalizing, externalizing, and pervasive developmental problems) and cognitive function. We combined phenotype and genotype data from 2 independent, population-based Dutch cohorts, yielding a total number of 1,495 to 3,175 of 3-, 7-, and 9-year-old children.
Significant SNP heritability estimates were found for attention-deficit/hyperactivity symptoms (SNP h(2) = 0.37-0.71), externalizing problems (SNP h(2) = 0.44), and total problems (SNP h(2) = 0.18), rated by mother or teacher. Sensitivity analyses with exclusion of extreme cases and quantile normalization of the phenotype data decreased SNP h(2) as expected under genetic inheritance, but they remained statistically significant for most phenotypes.
We provide evidence of the influence of common SNPs on child behavior problems in an ethnically homogenous sample. These results support the continuation of large GWAS collaborative efforts to unravel the genetic basis of complex child behaviors.
The chromosome bands 15q24.1-15q24.3 contain a complex region with numerous segmental duplications that predispose to regional microduplications and microdeletions, both of which have been linked to ...intellectual disability, speech delay and autistic features. The region may also harbour common inversion polymorphisms whose functional and phenotypic manifestations are unknown. Using single nucleotide polymorphism (SNP) data, we detected four large contiguous haplotype-genotypes at 15q24 with Mendelian inheritance in 2,562 trios, African origin, high population stratification and reduced recombination rates. Although the haplotype-genotypes have been most likely generated by decreased or absent recombination among them, we could not confirm that they were the product of inversion polymorphisms in the region. One of the blocks was composed of three haplotype-genotypes (N1a, N1b and N2), which significantly correlated with intelligence quotient (IQ) in 2,735 children of European ancestry from three independent population cohorts. Homozygosity for N2 was associated with lower verbal IQ (2.4-point loss, p-value = 0.01), while homozygosity for N1b was associated with 3.2-point loss in non-verbal IQ (p-value = 0.0006). The three alleles strongly correlated with expression levels of MAN2C1 and SNUPN in blood and brain. Homozygosity for N2 correlated with over-expression of MAN2C1 over many brain areas but the occipital cortex where N1b homozygous highly under-expressed. Our population-based analyses suggest that MAN2C1 may contribute to the verbal difficulties observed in microduplications and to the intellectual disability of microdeletion syndromes, whose characteristic dosage increment and removal may affect different brain areas.
The Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD) is effective in increasing parental sensitivity and sensitive discipline, and aims to decrease child ...behavior problems. Changes in quality of parenting may be accompanied by effects on child stress levels. However, studies of VIPP-SD effects on child behavior problems have shown mixed results and there are no studies to date of the effect of the intervention on children's stress levels, as measured by hair cortisol concentration (HCC). Furthermore, differences in intervention effectiveness may be explained by differential susceptibility factors. We hypothesized that the effects of the VIPP-SD on child behavior problems might be moderated by currently available child polygenic scores of differential susceptibility (PGS-DS). In the current pre-registered trial, we randomly assigned 40% of
= 445 families with school-aged twin children to the intervention group. The VIPP-SD was successful in decreasing both children's conduct problems and HCC. Effects were not moderated by available child PGS-DS. We conclude that a brief, home-based video-feedback parenting intervention can decrease child behavior problems and affect the child's stress-related neuroendocrine system as assessed with hair cortisol. In future studies, more specific PGS-DS for externalizing behaviors should be used as well as parental PGS-DS.
Background
Lateral ventricular volume (LVV) enlargement has been repeatedly linked to schizophrenia; yet, what biological factors shape LVV during early development remain unclear. DNA methylation ...(DNAm), an essential process for neurodevelopment that is altered in schizophrenia, is a key molecular system of interest.
Methods
In this study, we conducted the first epigenome‐wide association study of neonatal DNAm in cord blood with LVV in childhood (measured using T1‐weighted brain scans at 10 years), based on data from a large population‐based birth cohort, the Generation R Study (N = 840). Employing both probe‐level and methylation profile score (MPS) approaches, we further examined whether epigenetic modifications identified at birth in cord blood are: (a) also observed cross‐sectionally in childhood using peripheral blood DNAm at age of 10 years (Generation R, N = 370) and (b) prospectively associated with LVV measured in young adulthood in an all‐male sample from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 114).
Results
At birth, DNAm levels at four CpGs (annotated to potassium channel tetramerization domain containing 3, KCTD3; SHH signaling and ciliogenesis regulator, SDCCAG8; glutaredoxin, GLRX) prospectively associated with childhood LVV after genome‐wide correction; these genes have been implicated in brain development and psychiatric traits including schizophrenia. An MPS capturing a broader epigenetic profile of LVV – but not individual top hits – showed significant cross‐sectional associations with LVV in childhood in Generation R and prospectively associated with LVV in early adulthood within ALSPAC.
Conclusions
This study finds suggestive evidence that DNAm at birth prospectively associates with LVV at different life stages, albeit with small effect sizes. The prediction of MPS on LVV in a childhood sample and an independent male adult sample further underscores the stability and reproducibility of DNAm as a potential marker for LVV. Future studies with larger samples and comparable time points across development are needed to further elucidate how DNAm associates with this clinically relevant brain structure and risk for neuropsychiatric disorders, and what factors explain the identified DNAm profile of LVV at birth.
A large volume of behavioral research has explored the variable number of tandem repeat (VNTR) polymorphism on the dopamine receptor D4 gene (DRD4). However, findings are inconsistent and there is no ...agreement about what constitutes "functional" and "less functional" variants at this locus. First, we systematically review studies exploring biological differences between DRD4 VNTRs (k=21). Second, we systematically review studies relating DRD4 variation to behavioral traits in population-based, non-clinical samples of children and adolescents (k=46; N=13,195), highlighting the various genotypic classifications previously used. Third, we use meta-analyses to examine associations of DRD4 VNTRs with five broadly-defined behavioral outcomes (externalizing and attention problems, executive function, social/emotional development, and "reactive" temperament). We identify a significant association of "longer" DRD4 variants with lower levels of executive function and social/emotional development, but not independent of the choice of genotypic classification. We suggest that until the functionality of DRD4 VNTRs is established, researchers should report all genotypic classifications to ensure full transparency and allow for further meta-analytic work.
In Wertz et al. (2019), parents' polygenic scores of educational attainment (PGS‐EA) predicted parental sensitive responses to the child's needs for support, as observed in a dyadic task (i.e., ...observed sensitivity). We aimed to replicate and expand these findings by combining longitudinal data, child genotype data and several polygenic scores in the Generation R Study. Mother–child dyads participated in two developmental periods, toddlerhood (14 months old; n = 648) and early childhood (3–4 years old, n = 613). Higher maternal PGS‐EA scores predicted higher observed sensitivity in toddlerhood (b = 0.12, 95% CI 0.03, 0.20) and early childhood (b = 0.16, 95% CI 0.08, 0.24). Child PGS‐EA was significantly associated with maternal sensitivity in early childhood (b = 0.11, 95% CI 0.02, 0.21), and the effect of maternal PGS‐EA was no longer significant when correcting for child PGS‐EA. A latent factor of PGSs based on educational attainment, intelligence (IQ) and income showed similar results. These polygenic scores might be associated with maternal cognitive and behavioral skills that help shape parenting. Maternal PGSs predicted observed sensitivity over and above the maternal phenotypes, showing an additional role for PGSs in parenting research. In conclusion, we replicated the central finding of Wertz et al. (2019) that parental PGS‐EA partially explains parental sensitivity. Our findings may be consistent with evocative gene–environment correlation (rGE), emphasizing the dynamic nature of parenting behavior across time, although further research using family trios is needed to adequately test this hypothesis.
We replicated the Dunedin study on the relation between the polygenic score for educational attainment and observed sensitivity but also showed that the children's genotypic make‐up has to be taken into account. Our results point to the role of evocative gene–environment correlation in the dynamic interactions between parents and children.
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