Mendelian randomization demonstrates a causal link between peripheral circulating acylcarnitines and intracranial aneurysms.

ABSTRACT

Intracranial aneurysm (IA) is the most prevalent type of cerebral vascular disease causing life-threatening subarachnoid hemorrhages (SAH). A long-term vascular structure remodeling is considered as the main pathophysiological feature of IAs. However, the causal factors triggering the pathophysiological process are not clear. Recently, the abnormalities of peripheral circulating proteins and metabolites have been found in IAs patients and associated with the ruptures. We comprehensively investigated the potential causal relationship between blood metabolites and proteins and IAs using the mendelian randomization (MR) analysis. We applied two-sample MR to explore the potential causal association between peripheral circulating metabolites (191 blood metabolites) and proteins (1398 proteins) and IAs using data from the FinnGen study and the GWAS datasets published by Bakker et al. We identified palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine as causal contributors of IAs and ruptures. Further two-step mediation MR analysis suggested that hypertension as one of the contributors of IAs and ruptures mediated the causal relationship between palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine and IAs. Together, our study demonstrates that blood metabolic palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine are causally linked to the formation and rupture of IAs. Hypertension partially mediates the causal effects.