Abstract
The topology of the functional brain network has been associated with several neuropsychiatric conditions. However, little is known about its genetic underpinnings, and whether this overlaps with brain structure and neuropsychiatric conditions. Hence, we conducted genome-wide association study across six graph metrics of the macroscale functional networks at global, hemispheric and regional levels and their hemispheric asymmetry in 54,030 individuals. We identified seven experiment-wide significant loci and pri-oritised ten candidate genes. Both global graph metrics and hemispheric asymmetry are modestly heritable, but phenotypically and genetically form two clusters. Furthermore, cortical macro- and microstructure are causally related to global graph metrics and asymmetry, respectively, suggesting a dual structural constraint on functional network organisation. Finally, amongst twelve common neuropsychiatric conditions, only autism was genetically correlated with graph metrics of the functional network, supporting phenotypic case-control differences in functional connectivity. Overall, our results suggest different genetic axes shaping different aspects of brain functional topology and demonstrate shared biology with brain structure and autism.
Competing Interest Statement
ADB has received speaker fee from Lundbeck. ETB has done consultancy work for SR One, Boehringer Ingelheim, Novartis, GlaxoSmithKline, Monument Therapeutics and Sosei Heptares. ETB and RAIB hold equity in and are directors of Centile Bioscience Inc.
Funding Statement
This research was supported by funding from the Simons Foundation for Autism Research Initiative, the Wellcome Trust (214322\Z\18\Z), Horizon-Europe R2D2-MH (grant agreement number 101057385), and UKRI (10063472), and the ImmunoMIND hub as part of the UKRI Mental Health Platform. For the purpose of open access, we have applied a CC BY public copyright licence to any author-accepted manuscript version arising from this submission. S.B.-C. also received funding from the Autism Centre of Excellence, the Templeton World Charitable Fund, the MRC and the National Institute for Health Research Cambridge Biomedical Research Centre. All research at the Department of Psychiatry in the University of Cambridge is supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312) and the NIHR Applied Research Collaboration East of England. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department. Some of the results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777394 for the project AIMS-2-TRIALS. This joint undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA and Autism Speaks, Autistica and the SFARI. A.D.B and J.G. was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724, and R248-2017-2003). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). R.R-G was funded by the EMERGIA Junta de Andalucia program (EMERGIA20_00139), the Plan de Consolidacion (CNS2023-14364) and the Plan de Generacion de Conocimiento from the Agencia Estatal de Investigacion (PID2021-122853OA-I00). S.L.V. was supported by the Max Planck Society through the Otto Hahn Award; the Helmholtz International BigBrain Analytics and Learning Laboratory (Hiball); the Jacobs foundation research fellowship; Hector foundation research development award.
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:
All imaging, genetic and demographic data for this study have been obtained from UK Biobank (www.ukbiobank.ac.uk). Access to this data can be requested from the UK Biobank access management team.
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
Data availability
All GWAS summary statistics for graph phenotypes will be made publicly accessible on University of Cambridge servers upon publication. Summary statistics for autism can be requested from Jakob Grove. Summary statistics for other neuropsychiatric conditions have been made publicly available through the relevant articles listed in Supplementary Table 5. Please refer to the data availability sections of the respective articles.
