Causal effects of lung function on brain cortical structure and subcortical structure: a two-sample univariate and multivariate Mendelian randomization study

Abstract

Background Lung function has been increasingly linked to overall health, including brain health, prompting the 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. Methods We conducted univariate 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 like smoking and education. Sensitivity analyses were performed to confirm the stability of our results, and we applied FDR correction for multiple comparisons. Results The univariate MR analysis revealed significant associations between lung function and brain structures. Higher FEV1 was associated with increased global cortical volume (β = 4428.037, SE = 610.453, p < 0.0001) and supramarginal thickness (β = 43.613, SE = 13.218, p = 0.001). FVC was similarly associated with increased global cortical volume (β = 3650.674, SE = 576.736, p < 0.0001) and parsopercularis thickness (β = 0.013, SE = 0.003, p < 0.0001). Multivariable MR confirmed these associations, even after adjusting for smoking and education. Significant associations persisted in subcortical regions, with higher FEV1 and FVC linked to increased brainstem volume (FEV1: β = 0.226, SE = 0.049, p < 0.0001; FVC: β = 0.203, SE = 0.044, p < 0.0001) and amygdala volume for FEV1/FVC (β = 0.075, SE = 0.025, p = 0.003). Sensitivity and pleiotropy analyses indicated no significant heterogeneity or horizontal pleiotropy, confirming the robustness of the results. Conclusion 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. However, the reliance on European GWAS data limits generalizability, and some associations did not survive stringent correction. Future research should incorporate diverse populations and explore underlying mechanisms to validate and extend these findings.