FGF23 and Immune Cell Signatures Causally Linked to Subarachnoid Hemorrhage: Evidence From Multi-Omics and Genetic Colocalization.

BACKGROUND: Inflammation and immune response significantly contribute to brain injury following subarachnoid hemorrhage (SAH), a severe neurological condition. This study employed Mendelian randomization, colocalization, and multi-omics analysis to examine potential causal connections between inflammatory proteins, immune cells, and SAH, aiming to elucidate its pathogenesis. METHODS: This study utilized publicly available data from genome-wide association studies (GWAS), including protein QTL (pQTL) and RNA sequencing data. Bidirectional two-sample Mendelian Randomization (MR) analysis was initially employed to evaluate the cause-and-effect relationships among inflammatory proteins, immune cells, and SAH. A comprehensive multi-omics approach, encompassing transcriptome, colocalization, mediation MR, was employed to identify specific inflammatory proteins, immune cells, and potential drug targets. RESULTS: A causal relationship between five inflammatory proteins and SAH was identified through MR analysis (CD6, FGF23, TGFB-1, LIFR, and TGF-α). Moreover, a causal relationship with SAH was identified in 22 types of immune cells. Subsequent multi-omics analysis showed that FGF23 was a hub inflammatory protein, and its expression level was closely linked to the amount of CD4 Treg cells. Meta-analysis and replication studies identified FGF23 as a risk factor for SAH, with a colocalization score of 0.74. CONCLUSION: This study successfully identified inflammatory proteins and immune cells associated with SAH, and revealed the complex genetic causality and drug targets of SAH.