Genetic and phenotypic heterogeneity in early neurodevelopmental traits in the Norwegian Mother, Father and Child Cohort Study

Different neurodevelopmental conditions such as autism and ADHD frequently co-occur. Overlapping traits and shared genetic liability are potential explanations. We examine this using data from the population-based Norwegian Mother, Father, and Child Cohort study (MoBa), leveraging item-level data to explore the phenotypic factor structure and genetic architecture underlying neurodevelopmental traits at age 3 years (N = 41 708 – 58 630). We identified 11 latent factors at the phenotypic level using maternal reports on 76 items assessing children’s motor skills, language, social functioning, communication, attention, activity regulation, and flexibility of behaviors and interests. These factors showed associations with diagnoses of neurodevelopmental conditions and most shared genetic liabilities with autism, ADHD, and/or schizophrenia. Item-level GWAS revealed trait-specific genetic correlations with autism (item r g range = -0.27 – 0.78), ADHD (item r g range = -0.40 – 1), and/or schizophrenia (item r g range = -0.24 – 0.34). Based on patterns of item-level genetic covariance and genomic factor analyses, we find little evidence of common genetic liability across all neurodevelopmental traits. These results more so support genetic factors across more specific areas of neurodevelopment, some of which, such as prosocial behavior overlap with factors found in the phenotypic analyses. Other areas such as motor development seemed to have more heterogenous etiology, with indicators in this domain showing a less consistent pattern of genetic correlations with each other. Overall, these exploratory findings emphasize the etiological complexity of neurodevelopmental traits at this early age. In particular, diverse associations with neurodevelopmental conditions and genetic heterogeneity could inform follow-up work to identify shared and differentiating factors in the early manifestations of neurodevelopmental traits, which in turn could have implications for clinical screening tools and programs. ### Competing Interest Statement Co-author Ole A. Andreassen is a consultant of cortechs.ai, and has received speaker's honorarium from Lundbeck, Janssen and Sunovion with no conflict of interest relevant to this work. The other authors declare no conflicts of 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), ADA (2020023), AH (#2020022), LJH (#2019097, #2922083), and ECC (#2021045). The Research Council of Norway supported AH, RBA, and ECC (#274611), HA (#324620), and OAA (##324499, #324252). HA was supported by NordForsk (#156298). AR was supported by the Simons Foundation Autism Research Initiative (724306). ### 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 current study was approved by The Regional Committees for Medical and Health Research Ethics (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.