Causal effects of lung function on brain cortical and subcortical structure: a two-sample univariable and...

Lung function has been increasingly linked to brain health, prompting investigation into the causal relationships between lung function and brain structures. This study employs Mendelian Randomization (MR) to explore these causal relationships, leveraging genetic variants as proxies to predict the effects of lung function on brain cortical and subcortical structures.

We conducted univariable and multivariable MR analyses using GWAS summary statistics for lung function (FEV1, FVC, FEV1/FVC) and brain structures from the UK Biobank and ENIGMA consortium. Our analyses included five MR methods-IVW, MR-Egger, weighted median, weighted mode, and simple mode-to ensure robust causal inference. Multivariable MR (MVMR) analyses were performed to adjust for potential confounders. Sensitivity analyses were performed to confirm the stability of our results, and we applied Bonferroni correction for multiple comparisons.

The univariable MR analysis revealed significant associations between lung function and brain structures. Higher FEV1 was associated with increased global cortical surface area (β = 4428.037, SE = 610.453, p = 4.056E-13), higher FVC with increased global cortical surface area (β = 3650.674, SE = 576.736, p = 2.453E-10), and higher FEV1/FVC with increased paracentral surface area (β = 13.076, SE = 3.538, p = 2.193E-04). FVC was similarly associated with increased parsopercularis thickness (β = 0.013, SE = 0.003, p = 1.160E-04). Significant associations persisted in subcortical regions, with higher FEV1 and FVC linked to increased brainstem volume (FEV1: β = 0.226, SE = 0.049, p = 3.617E-06; FVC: β = 0.203, SE = 0.044, p = 4.158E-06). Multivariable MR confirmed these associations, even after adjusting for smoking, education, socioeconomic status, and physical activity. Significant associations persisted in cortical surface area, with higher FVC linked to increased global cortical surface area, and increased paracentral surface area for FEV1/FVC. Sensitivity and pleiotropy analyses indicated no significant heterogeneity or horizontal pleiotropy, confirming the robustness of the results.

Our study provides robust evidence of a causal relationship between lung function and brain structure, emphasizing the protective effects of better respiratory health on brain integrity.