Preprints

Abstract

Background Parental genetics matters for children’s behavioural difficulties, but the extent to which this is due to direct genetic transmission versus environmentally mediated indirect genetic effects remains unclear. Methods We studied eight European birth cohorts with over 33,000 family-based trio samples. We analysed polygenic scores (PGSs) for 13 mental health and neurodevelopmental conditions and their composite indices (PC1 and mean) representing general neuropsychiatric liabilities, as well as educational attainment (EA) and alcohol and cigarette use, from children (PGSc), mothers (PGSm), and fathers. Child internalising, externalising, and total difficulties reported by mothers and/or fathers were examined at preschool and school ages. We then conducted multivariate meta-analyses to combine cohort-level results. Findings We observed several direct genetic effects on externalising difficulties, while indirect genetic influences were mainly identified for internalising difficulties. Specifically, child PGSs for attention-deficit/hyperactivity disorder (ADHD) and EA predicted higher and lower levels, respectively, of child externalising and total difficulties (all pFDR<0·001; for school-aged externalising difficulties, PGSc-ADHD: β=0·121 [95% CI 0·091 to 0·151], pFDR<0·0001; PGSc-EA: β=−0·095 [95% CI −0·127 to −0·063], pFDR<0·0001), whereas maternal PGSs for major depressive disorder (MDD) and general neuropsychiatric liabilities were associated with internalising and total difficulties across parental raters and child ages (all pFDR<0·05; for school-aged internalising difficulties, PGSm-MDD: β=0·049 [95% CI 0·017 to 0·081], pFDR=0·016; PGSm-PC1: β=0·056 [95% CI 0·022 to 0·091], pFDR=0·011). No statistically significant effects from paternal PGSs were identified. Interpretation In this multi-cohort study, findings across multiple traits, raters, and ages supported several direct genetic effects of ADHD and EA on child externalising difficulties and indirect genetic effects on internalising difficulties, especially maternal depression and general neuropsychiatric liabilities. These suggest that child internalising difficulties are not solely driven by direct genetic transmission. More comprehensive research is needed to better understand the mechanisms involved, and ultimately how to ameliorate child behavioural difficulties.

Abstract

Social behaviour is a heritable, context-dependent trait that changes across social settings and development, influencing wellbeing and mental health. We present the first genome-wide meta-regression study of social behaviour from infancy to early adulthood, leveraging 491,246 repeat measures of low prosocial behaviour and peer/social difficulties in European-ancestry cohorts (Neff=121,777, Nind=73,321). We modelled heterogeneity in genetic effects across social domains, informants, and ages (2–29 years), capturing social context through genomic influences. Six loci were identified, including variation within CADM2 (p=2.51x10-9). The SNP-based heritability was modest (2–7%), and the genetic architecture of social behaviour multidimensional. Polygenic scores demonstrated predictability and accuracy in independent European-ancestry cohorts and, partially, in African-ancestry cohorts (Nind=16,305). Genetic correlations with later-life and mental health outcomes showed context-dependent patterns. Modelling predicted onsets of associations with social behaviour revealed distinct profiles, as observed for autism, ADHD, depression and schizophrenia, highlighting novel opportunities to genetically proxy developmental trajectories.

Abstract

Changes in the dynamics of chromatin state that control spatiotemporal gene expression patterns are crucial during brain development. CHD3 is a chromatin remodeler that is highly expressed during neurogenesis and that functions as a core member of the NuRD complex, a large multiprotein complex mediating chromatin state. Genetic disruptions in CHD3 have been implicated in a neurodevelopmental disorder characterized by intellectual disability, macrocephaly and severe speech deficits. To study the roles of CHD3 during early human brain development, we generated induced pluripotent stem cells with heterozygous and homozygous loss-of-function mutations, differentiated them into unguided neural organoids and cortical neurons, and analyzed these by immunohistochemistry, bulk RNA-, single-cell RNA-, and ChIP-sequencing. Loss of CHD3 expression had no detectable effects on early neuroepithelium formation and organoid growth, nor did it significantly affect cell type composition or neuronal differentiation speed. Instead, upon loss of CHD3, we observed dysregulation of genes related to axon guidance and synapse development across all datasets, identifying a novel role for the protein as a regulator that facilitates neurogenesis, in particular neuronal maturation. Our results based on genetically engineered knockout organoids pave the way for future studies modeling the neurobiological pathways affected in CHD3-related disorder.