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Genetic basis of the circle of Willis characteristics in the healthy and intracranial aneurysm population

European Journal of Human Genetics (2026) Cite this article

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A Comment to this article was published on 25 April 2026

Abstract

Rupture of an intracranial aneurysm (IA) can result in aneurysmal subarachnoid hemorrhage (ASAH), a severe and often fatal form of stroke. The configuration of the intracranial arteries – collectively known as the circle of Willis (CoW) – influences the risk of IA development and rupture. Although CoW variation is known to be heritable, its genetic underpinnings and contribution to IA remain poorly understood. Here, we aimed to investigate the genetic architecture of CoW variation and its potential link with IA. Using a semi-automated detection tool, we characterized the diameters, bifurcation angles, and presence of arterial segments of the CoW in 1078 participants from a population-based cohort and 682 IA patients. Composite traits capturing variation in all CoW characteristics were generated through principal component analysis. We conducted a genome-wide association study (GWAS) on these composite traits and identified four loci with suggestively significant associations. Lead single-nucleotide polymorphisms (SNPs) were located in or near the genes DPYSL2, CSMD3, TRPC6, and PKD1L2. Notably, PKD1L2 is closely related to PKD1, a gene implicated in autosomal dominant polycystic kidney disease, a connective tissue disorder that increases IA susceptibility. We observed statistically significant SNP-based heritability for the second principal component of CoW variation (heritability estimate = 0.95, standard error = 0.25). All lead SNPs demonstrated nominal association (p < 0.05) with multiple CoW characteristics and other vascular traits. Our findings highlight a substantial genetic contribution to CoW morphology and offer new insights into the molecular mechanisms underlying CoW variation and its role in IA pathogenesis.

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Fig. 1: Study overview.
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Fig. 2: Genome-wide association study of composite traits.
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Data availability

All GWAS summary statistics are available at https://doi.org/10.5281/zenodo.15084068. All other data generated in this study are included in the manuscript and the supplementary files. Individual-level data from the SHIP study can be accessed through a data application form available at https://fvcm.med.uni-greifswald.de/ for researchers who meet the criteria for access to confidential data.

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Acknowledgements

We thank Sofie H.J. Huigen MSc and Dennis P. Maas MSc for their valuable technical support in this project.

Funding

We acknowledge the support by the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 852173) and the Dutch Heart Foundation (Dekker Postdoc Grant 03-006-2023-0110 and Dekker Established Clinical Investigator Grant 03-001-2022-0157). SHIP is part of the Community Medicine Research Net of the University Medicine Greifswald, which is supported by the German Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. Whole body MR-imaging was supported by a joint grant from the Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg of Pomerania. AT has been funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 542489987.

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Authors and Affiliations

  1. Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht, The Netherlands

    Mark K. Bakker, Phebe J. Groenheide, Qi Chang Lin, Marloes H. A. Nanninga, Erwin Bekema, Jan H. Veldink & Ynte M. Ruigrok

  2. Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands

    Phebe J. Groenheide & Birgitta K. Velthuis

  3. Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands

    Iris N. Vos, Alina Guzu, Barbara Paic & Hugo J. Kuijf

  4. Translational Neuroimaging Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands

    Tessa A. Verhoeff

  5. Center of Excellence in Rehabilitation Medicine, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University and De Hoogstraat Rehabilitation, Utrecht, The Netherlands

    Tessa A. Verhoeff

  6. DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany

    Alexander Teumer & Uwe Völker

  7. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany

    Alexander Teumer & Hans J. Grabe

  8. Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany

    Robin Bülow

  9. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany

    Uwe Völker

  10. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

    Henry Völzke

  11. German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany

    Hans J. Grabe

Authors
  1. Mark K. Bakker
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  2. Phebe J. Groenheide
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  3. Iris N. Vos
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  8. Tessa A. Verhoeff
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  9. Erwin Bekema
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  10. Alexander Teumer
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  16. Birgitta K. Velthuis
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  18. Ynte M. Ruigrok
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Contributions

Conceptualization: MKB, YMR. Formal analysis: MKB, SHJH, DPM. Resources or data curation: MKB, INV, PJG, QCL, MHAN, AG, BP, TAV, EB, AT, RB, UV, HV, HJG, JHV, YMR. Writing – original draft: MKB. Writing – review & editing: MKB, QCL, PJG, AT, HV, JHV, YMR. Supervision: HJK, BV, YMR.

Corresponding author

Correspondence to Mark K. Bakker.

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Competing interests

The authors declare no competing interests.

Ethical approval

Ethical approval was obtained from all participants. All individuals from the SHIP study provided written informed consent, and the study was approved by the Ethics Committee of the University Medicine Greifswald, Germany (approval number BB 39/08). For the IA patient cohort, the study was approved by the Netherlands Medical Research Ethics Committee NedMec in consultation with the Biobank Research Ethics Committee of the UMC Utrecht.

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Bakker, M.K., Groenheide, P.J., Vos, I.N. et al. Genetic basis of the circle of Willis characteristics in the healthy and intracranial aneurysm population. Eur J Hum Genet (2026). https://doi.org/10.1038/s41431-026-02079-w

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