Multiomics Integration of Mendelian Randomization Identifies Circulating Metabolites Causally Linked to Intracranial Aneurysm.

Abstract

This study aimed to identify blood metabolites with potential causal effects on intracranial aneurysm (IA) risk using Mendelian randomization (MR) and to elucidate underlying molecular mechanisms via transcriptomic integration and experimental validation. Exposure data were derived from publicly available metabolomic genome-wide association study datasets. MR analyses, including inverse variance weighted, MR-Egger, and weighted median methods, were applied to evaluate causal associations between metabolites and IA, followed by sensitivity testing. Significant metabolites were annotated using the Kyoto Encyclopedia of Genes and Genomes database and intersected with differentially expressed genes from the Gene Expression Omnibus dataset GSE13353. Functional enrichment and protein-protein interaction network analyses were conducted to identify hub genes, which were further validated by quantitative polymerase chain reaction in whole blood samples from unruptured IA patients (n = 11) and healthy controls (n = 5). MR analysis identified 26 circulating metabolites significantly associated with unruptured IA, primarily involved in lipid metabolism, amino acid metabolism, and epigenetic regulation. Kyoto Encyclopedia of Genes and Genomes annotation yielded 3823 genes, of which 160 overlapped with differentially expressed genes from GSE13353. Enrichment analysis revealed significant involvement in mitogen-activated protein kinase signaling, leukocyte migration, and oxidative stress response. Based on integrated multiomics analysis and biological relevance, CXCL8, SPP1, and MMP9 were selected as key candidate genes. All 3 were significantly upregulated in IA patients as confirmed by quantitative polymerase chain reaction (P < 0.01). This study identifies metabolite-gene signatures associated with IA and reveals candidate biomarkers and therapeutic targets, providing novel insights into IA pathogenesis and avenues for metabolic intervention.