Triangular Causality Among Pulmonary Hypertension, Sleep Disorders, and Brain Structure at the Genetic Level: A Mendelian Randomization Study Focused on the Lung-Brain Axis.

Abstract

Background: The bidirectional relationship between pulmonary hypertension (PH) and sleep disorders has attracted significant research attention. The concept of the lung-brain axis has further highlighted the need for a holistic approach to managing these diseases.

Methods: This study used bidirectional two-sample Mendelian Randomization (MR) to explore the genetic-level causal relationships between PH, sleep disorders, and structural brain changes. GWAS data for PH were pooled from four cohorts; data on four sleep disorder subtypes were sourced from the FinnGen database; and data on 15 structural brain changes were obtained from the ENIGMA Consortium. To ensure reliability, we applied strict data selection, multiple corrections, heterogeneity assessments, and sensitivity tests. Visualizations included forest plots, scatter plots, funnel plots, and leave-one-out plots.

Results: MR analysis revealed a significant causal relationship between PH and both obstructive sleep apnea (OSA) (OR = 1.022, 95% CI = 1.006-1.039, P = 0.006, PBonferroni = 0.025) and general sleep disorders (OR = 1.018, 95% CI = 1.003-1.033, P = 0.018, PFDR = 0.036), with no evidence of reverse causation and multivariable MR analyses also demonstrated significant results. PH was linked to changes in total brain volume (P = 0.032) and cerebral white matter (P = 0.035). Amygdala changes appeared to reduce the risk of sleep disorders (P = 0.008) and OSA (P = 0.014). Sensitivity analyses showed no heterogeneity, pleiotropy, or significant outliers.

Conclusion: This study identifies significant causal links between PH, sleep disorders, and structural brain changes, establishing a triangular cyclic relationship that supports the lung-brain axis concept. These findings inform clinical management of PH and its comorbidities.