Causal associations between hypertension and abnormal brain cortical structures: Insights from a bidirectional Mendelian randomization study

Abstract

Background: Observational studies suggest that hypertension affects brain cortical structure. However, the potential causal association has yet to be entirely determined. Thus, we aim to assess the causality between hypertension and abnormal cortical structure.

Methods: We conducted a bidirectional Mendelian randomization (MR) study to estimate their relationship. Genome-wide association study summary statistics of hypertension (n = 484,598) and brain cortical (surface area and thickness) (n = 51,665) were derived from publicly available databases. Sensitivity analyses were applied to ensure the robustness of the results.

Results: The study showed that hypertension was associated with a decline in total brain cortical thickness [β, -0.0308 mm; 95 % confidence interval (CI), -0.0610 to -0.0007; p = 0.045] and the insula thickness [β, -0.0415 mm; 95 % CI, -0.0772 to -0.0057; p = 0.023]. A null association was observed between hypertension and other brain regions. In the reverse MR analysis, the total cortical surface area (per 1 SD increase) significantly decreased the incidence of hypertension [odds ratio (OR), 0.976; 95 % CI, 0.963 to 0.990; p = 5.15E-04]. The caudal anterior cingulate cortex thickness (per 1 SD increase) was significantly associated with an increased risk of hypertension [OR, 1.057; 95 % CI, 1.034 to 1.082; p = 1.08E-06]. Moreover, we found several nominally associated gyri, including cuneus, isthmus cingulate, middle temporal, para hippocampal, posterior cingulate, superior temporal, and medial orbitofrontal, influence the incidence of hypertension.

Conclusion: Our study showed causal relationships between hypertension and changes in specific brain cortical, providing new evidence for the heart-brain axis theory.

Keywords: Brain cortical; Caudal anterior cingulate cortex; Heart-brain axis; Hypertension; Insula; Mendelian randomization.

Graphical abstract

Fig. 1

Diagram of the bidirectional Mendelian randomization study for the causal relationship between hypertension and alteration in brain cortical structure. MR, mendelian randomization; SNP, single nucleotide polymorphism; SA, surface area; TH, thickness; MR-PRESSO, MR pleiotropy residual sum and outlier.

Fig. 2

The significant and nominally significant causalities in the bidirectional Mendelian randomization analysis. OR, odds ratio; CI, confidence interval; SNP, single nucleotide polymorphism; SA, surface area; TH, thickness.

Fig. 3

IVW estimates the causal relationship between hypertension and brain cortical structure. (A) represent the causal effect of hypertension on cortical structure. (B) represent the causal effect of cortical structure on hypertension. The colour of each block represents the p-value of every MR analysis. The red blocks indicate a p-value <0.05, and the blue blocks indicate a p-value ≥0.05. At the global level, a p-value <0.0125 is considered significant, whereas a p-value <3.68E-04 is considered significant at the regional level. The p-value lesser than 0.05 is considered nominally significant.

Fig. 4

Using a framework for visualizing the results of bidirectional Mendelian randomization analysis, we reveal the connections of hypertension and brain cortical structure alteration, providing new evidence for the theory of heart-brain axis. SA, surface area; TH, thickness.