Abstract

Early-life musical engagement is an understudied but developmentally important and heritable precursor of later (social) communication and language abilities. This study aims to uncover the aetiological mechanisms linking musical to communication abilities. We derived polygenic scores (PGS) for self-reported beat synchronisation abilities (PGSrhythmicity) in children (N≤6,737) from the Avon Longitudinal Study of Parents and Children and tested their association with preschool musical (0.5-5 years) and school-age (social) communication and cognition-related abilities (9-12 years). We further assessed whether relationships between preschool musicality and school-age communication are shared through PGSrhythmicity, using structural equation modelling techniques. PGSrhythmicity were associated with preschool musicality (Nagelkerke-R2=0.70-0.79%), and school-age communication and cognition-related abilities (R2=0.08-0.41%), but not social communication. We identified links between preschool musicality and school-age speech-and syntax-related communication abilities as captured by known genetic influences underlying rhythmicity (shared effect β=0.0065(SE=0.0021), p=0.0016), above and beyond general cognition, strengthening support for early music intervention programmes.

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.

Abstract

Mastering developmental milestones such as infant motor and personal-social skills (including social routines and pretend-play) can initiate a cascade of developmental changes that may affect language learning. Specifically, motor development may represent an important, but little understood “gateway” enabling children to interact with their environment. Here, we investigate how infant motor and personal-social abilities link to infant and toddler language performance, using a genetic perspective. For this, we studied measures of motor and personal-social skills (6 and 15 months) as predictors of language development, captured by ten language phenotypes (15-38 months) in genotyped children from the Avon Longitudinal Study of Parents and Children (N≤7,017). Language measures were combined into language factor scores (LFS) using structural equation modelling. Developmental genomic and non-genomic (residual) relationships across phenotypes were modelled with a Cholesky decomposition using genetic-relationship-matrix structural equation modelling (GRM-SEM). The ten early language measures were captured by three interrelated language factors (F-15M, F-24M, F-38M, 51.3% explained variance), each corresponding to a different age window. Across infant predictors and derived language factor scores, common genetic variation accounted for a modest proportion of the phenotypic variance (known as heritability, h2: gross-motor-abilities-6M-h2=0.18(SE=0.06), personal-social-skills-15M-h2=0.18(SE=0.06), LFS-15M-h2=0.12(SE=0.05), LFS-24M-h2=0.21(SE=0.06), LFS-38M-h2=0.17(SE=0.05)). Fitting a Cholesky GRM-SEM across predictors and LFS showed that infant gross motor abilities shared genetic influences with personal-social skills (factor loading λ; personal-social-skills-15M-λ=0.22(SE=0.09)), but were unrelated to language performance (P≥0.05). In contrast, genetic influences underlying personal-social skills, independent of gross motor skills, were related to all three LFS (LFS-15M-λ=0.26(SE=0.09), LFS-24M-λ=0.28(SE=0.10), LFS-38M-λ=0.30(SE=0.10)). GRM-SEM analyses studying individual language outcomes provided consistent results, both for genomic and non-genomic structures. Thus, aetiological processes linking motor to personal-social skills differ from those linking personal-social to language abilities, consistent with a developmental cascade where motor control enables children to engage in novel social interactions, but children’s social learning abilities foster language development.