Direct and Indirect Genetic Effects on Early Neurodevelopmental Traits

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The South-Eastern Norway Regional Health Authority supported LEH (#2020022), AH (#2020022), LJH (#2019097, #2922083), and ECC (#2021045). The Research Council of Norway supported AH(#274611, 336085, 300668), HA(#274611), ECC (#274611) and JHP (#324620). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The establishment of MoBa and initial data collection was based on a license from the Norwegian Data Protection Agency and approval from The Regional Committees for Medical and Health Research Ethics. The MoBa cohort is currently regulated by the Norwegian Health Registry Act. The Regional Committees for Medical and Health Research Ethics gave ethical approval for this work (2016/1702). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The consent given by the participants does not allow for storage of data on an individual level in repositories. Researchers can apply for access to data for replication purposes via MoBa, in line with MoBa data access policies.