Gurholt Tiril P, Elvsåshagen Torbjørn, Bahrami Shahram, Rahman Zillur, Shadrin Alexey, Askeland-Gjerde Daniel E, van der Meer Dennis, Frei Oleksandr, Kaufmann Tobias, Sønderby Ida E, Halvorsen Sigrun, Westlye Lars T, Andreassen Ole A
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.
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.
HGG Adv. 2025 Jan 9;6(1):100392. doi: 10.1016/j.xhgg.2024.100392. Epub 2024 Dec 10.
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.
虽然脑干区域是血压的中枢调节者，但其在高血压中作用的神经元机制仍知之甚少。在此，我们研究了全脑干和区域脑干体积与血压之间的结构和遗传关系。我们使用了来自n = 32666名英国生物银行参与者的磁共振成像数据，并评估了整个脑干及其主要区域的体积与血压的关联。我们将强大的统计遗传工具，包括双变量因果混合模型（MiXeR）和联合错误发现率（conjFDR），应用于英国生物银行队列中脑干体积（n = 27034）和血压（n = 321843）的非重叠全基因组关联研究。在调整整个脑干体积后，我们观察到整个脑干和延髓体积与收缩压和脉压之间呈负相关，中脑和脑桥体积与血压特征之间呈正相关（所有偏相关系数∣r∣效应在0.03至0.05之间，p≤0.0042）。我们观察到整个脑干的遗传重叠最大，其影响性状的变异中有77%与血压共享。我们在脑干体积和血压特征之间鉴定出65个共享位点，并将这些位点映射到71个基因，涉及与交感神经系统发育、金属离子转运和血管稳态相关的分子途径。本研究结果支持脑干结构与血压之间的联系，并为它们共同的遗传基础提供了见解。重叠的遗传结构和定位的基因提供了有关脑干区域在高血压中作用的机制信息。
