Venous Thromboembolism Attenuates Brain Cortical Thickness: Evidence from Mendelian Randomization Study

Background: Emerging evidence suggests an association between vascular risk factors and changes in brain cortical structure and function. However, the relationship between venous thromboembolism (VTE) and brain cortical remodeling remains unclear, impeding further research on brain cortical dysfunction. Methods: Using summary statistics obtained from genome-wide association studies (GWAS), we conducted two-sample Mendelian randomization (MR) analyses to explore potential causal effects of genetically predisposed pulmonary embolism (PE, N = 361,194), deep vein thrombosis (DVT, N = 462,933) and unspecified VTE (N = 218,792) on brain cortical structure (N = 51,665). Magnetic resonance imaging (MRI)-based measures of brain cortex including surface area (SA) and thickness (TH) were collected both globally and across 34 regional gyri. All participants were of European descent. Data analysis was conducted between June 2023 and September 2023. Results: Globally, the cortical TH was consistently reduced in patients with PE, DVT and VTE (β PE: –0.344 mm, 95% CI: –0.654 mm to –0.033 mm, P = 0.030; β DVT: –0.150 mm, 95% CI: –0.298 mm to –0.002 mm, P = 0.047; β VTE: –0.003 mm, 95% CI: –0.006 mm to –0.0003 mm, P = 0.029). Regionally, DVT specifically caused a decrease in cortical TH in the paracentral gyrus (β : –0.438 mm, 95% CI: –0.647 mm to –0.229 mm, Bonferroni-corrected P = 4.02 × 10–5). This decrease persisted even after global adjustment (β : –0.281 mm, 95% CI: –0.434 mm to –0.126 mm, Bonferroni-corrected P = 3.49 × 10–4). No pleiotropy or heterogeneity was detected. Conclusion: Our study shows a causal effect of genetically proxied VTE on brain cortical thinning. This finding supports previously established epidemiological associations between VTE and brain dysfunctions and offers mechanistic insight.