Abstract
Investigating the genetic underpinnings of functional brain connectivity is essential to understand how genetic variation influences brain health and disease. Here, a mass-univariate approach was adopted to study the genetic architecture of functional brain circuitry (Ntotal = 28,159 subjects) with high spatial resolution (82 brain regions). Common genetic variants explained individual differences in 33% of all 3321 inter-regional functional pathways with 72 significant associations reflecting widespread, pleiotropic effects across the connectome. These associations were mapped to five genes—PAX8, EphA3, SLC39A12, THBS1 and APOE—with known associations with brain phenotypes and which converged in biological processes related to neurodevelopment and cardiovascular and cognitive traits (enrichment minimum p = 3.0 × 10−6 and p = 1.6 × 10−5, respectively). Our findings show that the genetic component of individual differences in functional brain connectivity is largely shared throughout the brain, highlighting the importance of genetic variation in large-scale brain organisation and its relationship with cognitive function and overall health.
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Data availability
The genome-wide summary statistics data generated in this study can be accessed through https://doi.org/10.5281/zenodo.1842946089. The imaging and genotyping data are protected and are not available due to data privacy. The Source data used to plot each figure are provided with this paper. The following data have been used to perform the analyses on this manuscript: LD reference for LDSC, https://www.internationalgenome.org/category/reference/; RSN Annotation Files, https://surfer.nmr.mgh.harvard.edu/fswiki/CorticalParcellation_Yeo2011; MNI template: https://nist.mni.mcgill.ca/mni-average-brain-305-mri/; FLAMES pathway-naïve feature set: https://zenodo.org/records/10409723; Case-control disease sumstats: https://pgc.unc.edu/for-researchers/download-results/. Source data are provided with this paper.
Code availability
All used software tools and code are publicly available: CATO, http://www.dutchconnectomelab.nl/CATO/; FUMA, http://fuma.ctglab.nl/; MAGMA, https://ctg.cncr.nl/software/magma; LDSC, https://github.com/bulik/ldsc; PLINK, https://www.cog-genomics.org/plink/; FlashPCA2, https://github.com/gabraham/flashpca; FLAMES, https://github.com/Marijn-Schipper/FLAMES; FINEMAP & LDStore2, http://www.christianbenner.com/; coloc R package, https://chr1swallace.github.io/coloc/.
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Acknowledgements
B.A.P.C.M., D.P., C.R., M.P.vd.H., and M.S. were funded by a Dutch Research Council (NWO) Gravitation grant: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012 [to D.P.]). D.P. and C.d.L. were funded by a European Research Council advanced grant (grant no. ERC-2018-AdG GWAS2FUNC 834057 [to D.P.]). M.P.vd.H. and K.H. were funded by an European Research Council Consolidator grant: CONNECT (grant no. 101001062 [to M.P.vd.H]). M.P.vd.H. was funded by a Dutch Research Council (NWO) VICI grant: BrainDiversity (grant no. VI.C.241.074). J.E.S. is supported by the Dutch Research Council (NWO) VENI Grant 201G-064. This manuscript was submitted as a preprint to medRxiv. This research has been conducted using the UK Biobank resource under application 16406. We thank the numerous participants, researchers, and staff who collected and contributed to the data. We thank SURF for the support in using the National Supercomputers Snellius and LISA. Part of the work in this manuscript was carried out with the support of the SURF Cooperative using grant EINF-14888. We thank Dr Rachel M. Brouwer, Dr Sophie van der Sluis and Ilan Libedinsky for all the feedback. Finally, we would also like to acknowledge Dr Elleke P. Tissink and Dr Siemon C. de Lange, who preprocessed the MRI data.
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B.d.A.P.C.M.: Conceptualisation, Methodology, Formal Analysis, Writing, Visualisation. M.S.: Formal Analysis, Feedback. C.R.: Visualisation, Feedback. C.d.L.: Methodology, Feedback. K.H.: Feedback. D.P.: Funding acquisition, Feedback. J.E.S.: Methodology, Supervision, Feedback. M.P.v.d.H: Conceptualisation, Methodology, Resources, Supervision, Project Administration.
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M.P.v.d.H. works as a consultant for Hoffman-La Roche and is part of the editorial team of Wiley Human Brain Mapping; they had no role in this study. The authors declare no competing interests.
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Maciel, B.d.A., Schipper, M., Romero, C. et al. The genetic landscape of human functional brain connectivity. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69442-9
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DOI: https://doi.org/10.1038/s41467-026-69442-9
