Circulating proteins as key genetically proxied mediators in the pathway from smoking to intracranial aneurysm disease: A mediation Mendelian randomization analysis.

INTRODUCTION: The molecular mechanisms linking smoking to intracranial aneurysmal disease remain elusive. In this study, we aimed to employ Mendelian randomization (MR) analysis to identify proteomic pathways that mediate this relationship. METHODS: We conducted a two-step, two-sample MR study using summary-level GWAS data from the GSCAN (GWAS & Sequencing Consortium of Alcohol and Nicotine Use, release up to 2019) and the FinnGen study (release R12, 2024). In the first step, we estimated the effects of genetically proxied smoking, using the Lifetime Smoking Index (LSI) as the primary exposure, on circulating protein levels. In the second step, we assessed the associations of smoking-related proteins with the risk of unruptured intracranial aneurysms (uIAs) and aneurysmal subarachnoid hemorrhage (aSAH). Proteins that showed significant associations in both steps were considered potential mediators, and we calculated their mediation proportions using the product-of-coefficients method. RESULTS: Genetically proxied smoking was associated with increased risks of uIAs and aSAH. Each one standard deviation increase in LSI was associated with a 2.99-fold higher risk of uIAs (OR=2.99; 95% CI: 1.77-5.06) and a 2.51-fold higher risk of aSAH (OR=2.51; 95% CI: 1.72-3.66). After multiple-testing correction, LSI was causally associated with 427 circulating proteins; 22 correlated with aSAH and 22 with uIAs, with eight shared. Mediation analysis confirmed six mediators (CD74, HEG1, YAP1, FGF23, SFRP1, PGF) for the LSI-aSAH pathway and four (CD74, YAP1, ANGPT2, RTN4R) for the LSI-uIA pathway. CD74 and YAP1 were shared mediators with the highest mediation ratios. CONCLUSIONS: Eight distinct circulating proteins mediate smoking-induced intracranial aneurysm development and rupture via independent biological cascades. CD74 and YAP1 may serve as priority candidate mediators for future mechanistic and translational investigations aimed at refining risk stratification in smoking-related intracranial aneurysms.