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Genetic pathways linking oxytocin-vasotocin hypothalamic subunit architecture with psychiatric and metabolic traits

Molecular Psychiatry (2026)Cite this article

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Abstract

The neuropeptides oxytocin and vasotocin are predominantly produced in the supraoptic and paraventricular nuclei of the anterior-inferior, anterior-superior and tubular-superior hypothalamic subunits. Evidence suggests that oxytocin and vasotocin signaling play a role in both physiology and behavior, and that dysfunction of these signaling systems may contribute to the co-occurrence of metabolic and psychiatric conditions. The genetic pathways, however, that may underlie the connection between these physiological and behavioral traits are yet to be clearly delineated. We deployed bivariate mixture models and conjunctional FDR to estimate the global and local genetic overlap between three oxytocinergic-vasotocinergic hypothalamus subunits and ten psychiatric and metabolic traits related to oxytocin and vasotocin signaling. We show that these three subunits share moderate-to-extensive genetic overlap with the tested traits, therein stronger overlap with psychiatric than metabolic traits. We found most complete overlap between the anterior subunits and systolic blood pressure. Across all subunit and trait combinations, we pinpoint 95 novel, unique associated loci. The genes associated with these loci were enriched in gene sets linked to neuroimaging and neurodegeneration as well as metabolic markers, and were up-/down-regulated in tissues such as blood vessel and the liver. These findings help shed light on the genetic architecture of the hypothalamic subunits implicated in oxytocin and vasotocin and selected traits, and provide new avenues for future research.

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Fig. 1: Anatomy of the human hypothalamus.
Fig. 2: Estimated number of variants per trait.
Fig. 3: Genetic overlap of the bivariate MiXeR analyses.
Fig. 4: Manhattan plots for asHyp and the six traits that passed AIC/log-likelihood without UKB sample overlap.
Fig. 5: Tissue specific up- and down-regulation of genes associated with the asHyp and metabolic traits conjFDR analysis.

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Data availability

The external GWAS summary statistics data is partially publicly available for download at the consortium’s official websites (PGC: https://pgc.unc.edu/, GIANT consortium: https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium, DIAGRAM consortium: https://diagram-consortium.org/index.html). The internally generated GWAS summary statistics data for the three selected hypothalamus subunits are available at https://osf.io/k46gu/.

Code availability

Supplementary information, scripts used for analyses with information on specific parameter settings, and additional notes are available at https://osf.io/k46gu/.

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Acknowledgements

This research was funded by Research Council of Norway (301767). Figure 1 was created with https://app.biorender.com/ and Adobe Illustrator 2024–2026, the grid for the Venn diagrams in Fig. 3 was created in Adobe Illustrator 2024–2026. This work was partly performed on the TSD (“Tjenester for Sensitive Data”) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT) (tsd-drift@usit.uio.no). Computations were also performed on resources provided by UNINETT Sigma2 – the National Infrastructure for High-Performance Computing and Data Storage in Norway (NS9666S). All methods were performed in accordance with the relevant ethical guidelines and regulations.

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Authors and Affiliations

  1. Department of Psychology, University of Oslo, Oslo, Norway

    Alina I. Sartorius, Lars T. Westlye & Daniel S. Quintana

  2. Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Dennis van der Meer, Alexey Shadrin, Ole A. Andreassen & Lars T. Westlye

  3. K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo, Oslo, Norway

    Alexey Shadrin, Ole A. Andreassen, Terje Nærland, Lars T. Westlye & Daniel S. Quintana

  4. Centre of Research and Education in Forensic Psychiatry, Oslo University Hospital, Oslo, Norway

    Jaroslav Rokicki

  5. Department of Electronic Systems, Vilnius Tech, Vilnius, Lithuania

    Jaroslav Rokicki

  6. SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa

    Megan Campbell

  7. Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Megan Campbell

  8. Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway

    Adriano Winterton

  9. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany

    Emanuel Schwarz

  10. Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Emanuel Schwarz

  11. NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway

    Terje Nærland & Daniel S. Quintana

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  1. Alina I. Sartorius
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  2. Dennis van der Meer
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  11. Daniel S. Quintana
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Contributions

AIS, DSQ and DVDM conceived and planned the study. AIS analyzed the data, with contributions from JR for the hypothalamus subunits segmentation, AS for the GWAS, heritability, MiXeR and genetic correlation analyses, and DVDM for the conjFDR analyses. DSQ and DVDM supervised the study. DSQ provided funding for the study. AIS interpreted the results, with contributions from DSQ, DVDM, AS, JR, MC, AW, OAA, TN and LTW. AIS wrote the first and revised drafts of the manuscript, with DSQ, DVDM, AS, JR, MC, AW, OAA, ES, TN and LTW contributing to the first and revised drafts of the manuscript.

Corresponding author

Correspondence to Daniel S. Quintana.

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Competing interests

ES received speaker fees from bfd buchholz-fachingormationsdienst GmbH and Lundbeckfonden as well as editorial fees from Lundbeckfonden and the Wellcome Trust. All other authors declare no potential competing interests with respect to the research, authorship and/or publication of this article.

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Sartorius, A.I., van der Meer, D., Shadrin, A. et al. Genetic pathways linking oxytocin-vasotocin hypothalamic subunit architecture with psychiatric and metabolic traits. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03508-4

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