Direct and Indirect Genetic Effects on Early Neurodevelopmental Traits

Abstract

Background: Neurodevelopmental conditions are highly heritable and frequently co-occur within individuals. Recent studies have shown that SNP heritability estimates can be confounded by genetic effects mediated via the environment (indirect genetic effects). However, the relative importance of direct versus indirect genetic effects on early manifestations of neurodevelopmental conditions is unknown. Methods: The sample included up to 24,692 parent-offspring trios from the Norwegian MoBa cohort. We use Trio-GCTA to estimate latent direct and indirect genetic effects on mother-reported neurodevelopmental traits at age three years (restricted and repetitive behaviors and interests, attention, hyperactivity, language, social, and motor development). Further, we investigate to what extent direct and indirect effects are attributable to common genetic variants associated with autism, ADHD, developmental dyslexia, educational attainment, and cognitive ability using polygenic scores (PGS) in regression modeling. Results: We find evidence for contributions of direct and indirect latent common genetic effects contributing to attention (direct: explaining 4.8% of variance, indirect: 6.7%) hyperactivity (direct: 1.3%, indirect: 9.6%), and restricted and repetitive behaviors (direct effects: 0.8%, indirect effects: 7.3%). Variation in social and communication, language, and motor development was best explained by direct effects (5.1-5.7%). Direct genetic effects on attention were captured by PGS for ADHD, autism, educational attainment, and cognitive ability, whereas direct genetic effects on language development were captured by cognitive ability and autism PGS. Indirect genetic effects were primarily captured by educational attainment and/or cognitive ability PGS across all outcomes. Conclusions: Results were consistent with differential contributions to neurodevelopmental traits in early childhood by direct and indirect genetic effects. Indirect effects were particularly important for hyperactivity and restricted and repetitive behaviors and interests, and may be linked to genetic variation associated with cognition and educational attainment. Within-family approaches are important for disentangling genetic processes that influence early neurodevelopmental traits, even when identifiable associations are small.