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

Abstract

AbstractBackgroundWhile 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.MethodsUsing 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.ResultsWe 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.ConclusionsThe 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.