Large-scale brainstem neuroimaging and genetic analyses provide new insights into the neuronal mechanisms of hypertension
Tiril P. Gurholt,
Torbjørn Elvsåshagen,
Shahram Bahrami,
Zillur Rahman,
Alexey Shadrin,
Daniel E. Askeland-Gjerde,
Dennis van der Meer,
Oleksandr Frei,
Tobias Kaufmann,
Ida E. Sønderby,
Sigrun Halvorsen,
Lars T. Westlye,
Ole A. Andreassen
Affiliations
Tiril P. Gurholt
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway; Corresponding author
Torbjørn Elvsåshagen
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway; Department of Behavioural Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway
Shahram Bahrami
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Precision Psychiatry, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
Zillur Rahman
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Precision Psychiatry, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
Alexey Shadrin
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Precision Psychiatry, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
Daniel E. Askeland-Gjerde
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway
Dennis van der Meer
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Precision Psychiatry, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway; School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht 6200 MD, the Netherlands
Oleksandr Frei
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Precision Psychiatry, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
Tobias Kaufmann
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany; German Center for Mental Health (DZPG), Partner Site Tübingen, Tübingen, Germany
Ida E. Sønderby
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway
Sigrun Halvorsen
Department of Cardiology, Oslo University Hospital Ullevål and University of Oslo, 0424 Oslo, Norway
Lars T. Westlye
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Psychology, University of Oslo, 0373 Oslo, Norway
Ole A. Andreassen
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway; Center for Precision Psychiatry, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
Summary: 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. We used magnetic resonance imaging data from n = 32,666 UK Biobank participants, and 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 non-overlapping genome-wide association studies of brainstem volumes (n = 27,034) and blood pressure (n = 321,843) in the UK Biobank cohort. 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 partial correlation coefficients ∣r∣ effects between 0.03 and 0.05, p ≤ 0.0042). We observed the largest genetic overlap for the whole brainstem, sharing 77% of its trait-influencing variants with blood pressure. We identified 65 shared loci between brainstem volumes and blood pressure traits and mapped these to 71 genes, implicating molecular pathways linked to sympathetic nervous system development, metal ion transport, and vascular homeostasis. The present findings support a link between brainstem structures and blood pressure and provide insights into their shared genetic underpinnings. The overlapping genetic architectures and mapped genes offer mechanistic information about the roles of brainstem regions in hypertension.
