The association between reduced hypothalamic subregion volume and aortic aneurysm risk: a Mendelian randomization and multi-omics study with clinical MRI validation.

BACKGROUND

Aortic aneurysms represent significant cardiovascular pathologies with an incompletely understood pathogenesis. The hypothalamus, a critical structure in regulating autonomic functions, endocrine activity, and circadian rhythms, may play a role in this context.

METHODS

We used Mendelian randomization (MR) to test the causal effects of hypothalamic subregional volumes on aortic aneurysm risk. Utilizing T1-weighted MRI data from individuals with aortic aneurysms and healthy controls, we investigated group differences in the volumes of five hypothalamic subregions. Multiple analytical methods were combined to pinpoint the causative gene, followed by mediation analysis with cis-expression quantitative trait loci targets.

RESULTS

MR analysis revealed that hypothalamic volume reduction was genetically linked to higher aortic aneurysm risk: anterior superior (OR = 0.33, 95%CI: 0.13-0.81, FDR = 0.026), inferior tubular (OR = 0.52, 95%CI: 0.33-0.83, FDR = 0.026), and superior tubular (OR = 0.36, 95%CI: 0.16-0.80, FDR = 0.026). Brain MRI showed reduced superior tubular volume in aortic aneurysm patients versus controls (173.22 ± 20.99 mm3 vs 185.87 ± 20.90 mm3; p < 0.05, 95%CI: 0.941-0.998). Multiple analytical approaches identified candidate genes potentially related to aortic aneurysm and suggested that IL1B may act as a potential statistical mediator in the association between hypothalamic volume and aortic aneurysm risk.

CONCLUSIONS

The findings suggest that genetically predisposed structural changes in the hypothalamus, especially reduced superior tubular volume, are associated with a higher risk of aneurysms, and imply that the hypothalamus may affect aortic aneurysm development through an inflammatory pathway.