Multivariate patterns between brain network properties, polygenic scores, phenotypes, and environment in preadolescents

The brain network is an infrastructure for cognitive and behavioral processes. Genetic and environmental factors influence the development of the brain network. However, little is known about how specific genetic traits and children’s brain network properties are related. Furthermore, insight into the holistic relationship of brain network properties with genes, environment, and phenotypic outcomes in children is still limited. To fill these knowledge gaps, we investigated the multivariate associations between the brain network properties and three domains using a large youth sample (the ABCD study, N=9,393, 9-10 years old): (i) genetic predisposition of various traits, (ii) phenotypic outcomes, and (iii) environmental factors. We constructed structural brain networks using probabilistic tractography and estimated nodal and global network measures such as degree and network efficiency. We then conducted sparse canonical correlation analysis with brain network measures and polygenic scores of 30 complex traits (e.g., IQ), phenotypic traits (e.g., cognitive ability), and environmental variables. We found multivariate associations of brain network properties with (i) genetic risk for psychiatric disorders, (ii) genetic influence on cognitive ability, and (iii) the phenotype of cognitive ability-psychopathology in preadolescents. Our subsequent mediation analysis using the latent variables from the canonical correlation analysis showed that the influence of genetic factors for cognitive ability on the cognitive outcomes was partially mediated by the brain network properties. Taken together, this study shows the key role of the development of the brain structural network in children in cognitive development with its tight, likely causal, relationship with genetic factors. These findings may shed light on future studies of the longitudinal deviations of those gene-environment-brain network relationships in normal and disease conditions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021R1C1C1006503, 2021K2A9A1A01102014, 2021K1A3A1A21037512, 2021M3E5D2A01022515), by Seoul National University Research Grant in 2021 (No. 200-20210083), by Creative-Pioneering Researchers Program through Seoul National University (No. 200-20220046), by Semi-Supervised Learning Research Grant by SAMSUNG (No.A0426-20220118), by Institute of Information & communications Technology Planning & Evaluation (IITP) grant funded by the Korea government(MSIT) [NO.2021-0-01343, Artificial Intelligence Graduate School Program (Seoul National University)], and by Identify the network of brain preparation steps for concentration Research Grant by Looxid Labs (No.339-20230001). ### 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 study used ONLY openly available human data that were originally located at The Adolescent Brain and Cognitive Development (ABCD) study release 2.0 and 3.0 (). 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 All original data are publicly available from the NDA (). Mook data, which corresponds to the processed data used in this study, was generated from conditional GAN for tabular data ([Xu et al., 2019][1]) and are available from this site (). [1]: #ref-102