The genetic landscape of human functional brain connectivity

Bernardo de APC Maciel; Marijn Schipper; Cato Romero; Christiaan de Leeuw; Koen Helwegen; Danielle Posthuma; Jeanne E. Savage; Martijn P. van den Heuvel

doi:10.1038/s41467-026-69442-9

The genetic landscape of human functional brain connectivity

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Article number	3120
Pages (from-to)	1-12
Number of pages	12
Journal	Nature Communications
Volume	17
Early online date	24 Feb 2026
DOIs	https://doi.org/10.1038/s41467-026-69442-9
Publication status	Published - 2026

Funding

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. 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.

Funders	Funder number
European Research Council	ERC-2018-AdG GWAS2FUNC 834057, 201G-064, 101001062, 16406
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	024.004.012
SURF	EINF-14888

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title = "The genetic landscape of human functional brain connectivity",

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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AU - Maciel, Bernardo de APC

AU - Schipper, Marijn

AU - Romero, Cato

AU - de Leeuw, Christiaan

AU - Helwegen, Koen

AU - Posthuma, Danielle

AU - Savage, Jeanne E.

AU - van den Heuvel, Martijn P.

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AB - 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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The genetic landscape of human functional brain connectivity

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