Genetic influences on the intrinsic and extrinsic functional organizations of the cerebral cortex

The human cerebral cortex plays a crucial role in brain functions. However, genetic influences on the human cortical functional organizations are not well understood. Using a parcellation-based approach with resting-state and task-evoked functional magnetic resonance imaging (fMRI) from 40,253 individuals, we identified 47 loci associated with functional areas and networks at rest, 15 of which also affected the functional connectivity during task performance. Heritability and locus-specific genetic effects patterns were observed across different brain functional areas and networks. Specific functional areas and networks were identified to share genetic influences with cognition, mental health, and major brain disorders (such as Alzheimer’s disease and schizophrenia). For example, in both resting and task fMRI, the APOE ε4 locus strongly associated with Alzheimer’s disease was particularly associated with the visual cortex in the secondary visual and default mode networks. In summary, by analyzing biobank-scale fMRI data in high-resolution brain parcellation, this study advances our understanding of the genetic determinants of cerebral cortex function and prioritizes genetically associated fMRI traits for clinical applications of specific brain disorders. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was partially supported by U.S. NIH grants MH086633 (HT.Z.) and MH116527 (TF.L. and HP.Z.). HCP data were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. ### 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 UKB study had obtained ethics approval from the North West Multicentre Research Ethics Committee (approval number: 11/NW/0382). All experimental procedures in the HCP study were approved by the institutional review boards at Washington University (approval number: 201204036). 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Our GWAS summary statistics will be shared on Zenodo and at BIG-KP . The individual-level data used in the present study can be applied from the UK Biobank () and HCP ().