Exploring the bidirectional relationships between MRI resting-state functional connectivity networks and...

Brain functional connectivity alterations have been observed in cardiovascular diseases (CVDs), but the causality between brain resting-state functional connectivity networks and CVDs remains undetermined. We aimed to investigate the bidirectional causality between brain network connectivity and CVDs using Mendelian randomization (MR) analysis.

Using genome-wide association study (GWAS) data from the UK Biobank (n = 34,691), we conducted bidirectional two-sample MR analyses between 191 resting-state functional MRI phenotypes and four major CVDs: hypertension, atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD). Sensitivity analyses, including MR-Egger regression and weighted median methods, were conducted to ensure the robustness of causal estimates and to test for potential pleiotropy.

For hypertension, four networks showed negative causal associations (ORs 0.882-0.904), primarily involving motor, subcortical-cerebellar, default mode, and visual networks. In AF, we observed both increased connectivity in salience and default mode networks (ORs 1.157-1.288) and decreased connectivity in visual-motor networks (OR 0.790). For HF, three networks showed significant associations: decreased connectivity in visual and temporal networks (ORs 0.791-0.804) and increased connectivity in motor networks (OR 1.352). CAD was associated with increased connectivity in both default mode and central executive networks (ORs 1.145-1.147). These relationships remained robust after multiple sensitivity analyses.

Our findings reveal novel bidirectional causal relationships between specific brain functional networks and CVDs, with distinct patterns of network involvement for different CVDs suggesting disease-specific mechanisms in the cardio-cerebral axis. These findings identify potential neuroimaging biomarkers for early detection and monitoring of cardiovascular diseases.