Large-scale brainstem neuroimaging and genetic analyses provide new insights into the neuronal mechanisms of hypertension

Background While brainstem regions are central regulators of blood pressure, the neuronal mechanisms underlying their role in hypertension remain poorly understood. Here, we investigated the structural and genetic relationships between global and regional brainstem volumes and blood pressure. Methods Using magnetic resonance imaging data from n=32,666 UK Biobank participants, we assessed the association of volumes of the whole brainstem and its main regions with blood pressure. We applied powerful statistical genetic tools, including bivariate causal mixture modeling (MiXeR) and conjunctional false discovery rate (conjFDR), to summary statistics from genome-wide association studies of brainstem volumes (n=27,034) and blood pressure (n=318,891) and evaluated their genetic architectures. Results We observed negative associations between the whole brainstem and medulla oblongata volumes and systolic blood and pulse pressure, and positive relationships between midbrain and pons volumes and blood pressure traits when adjusting for the whole brainstem volume (all ∣r∣ 0.03-0.05, p≤0.0042). We observed the largest genetic overlap for the whole brainstem, sharing between 54% and 69% of its trait-influencing variants with blood pressure. We identified 42 shared loci between brainstem volumes and blood pressure traits and mapped these to 83 genes, implicating molecular pathways linked to the development of the brainstem, cranial nerves, and sympathetic neurons, and to metal ion transport and cell-matrix adhesions. Conclusions The present findings support a link between brainstem structures and blood pressure and provide new insights into their shared genetic underpinnings. The overlapping genetic architectures and mapped genes offer new mechanistic information about the roles of brainstem regions in hypertension. ### Competing Interest Statement OAA has received a speaker's honorarium from Lundbeck, Janssen, and Synovion, and is a consultant to Cortechs.ai. TE is a consultant to BrainWaveBank and Synovion and received speaker's honoraria from Lundbeck and Janssen Cilag. The remaining authors declare no conflict of interest. ### Funding Statement We obtained funding from the Research Council of Norway (#223273, #326813, #324252, #324499, #323961); South-Eastern Norway Regional Health Authority (#2017112; #2022080); German Federal Ministry of Education and Research (BMBF, #01ZX1904A); European Union's Horizon2020 Research and Innovation Programme (CoMorMent project; Grant #847776) and European Research Council (ERC) StG (Grant #802998). We performed this work on the Services for sensitive data (TSD), University of Oslo, Norway, with resources provided by UNINETT Sigma2 - the National Infrastructure for High-Performance Computing and Data Storage in Norway. ### 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: The UK Biobank obtained informed consent from all participants, has IRB approval from the North West Multi-center Research Ethics Committee, and the Ethics Advisory Committee () oversees the UK Biobank Ethics &; Governance Framework. We obtained access to the UK Biobank cohort through Application number 27412. We have approval from the Regional Committees for Medical and Health Research Ethics in Norway. 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][1]. 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 [1]: http://ClinicalTrials.gov