Causal relationship between mental disorders and abdominal aortic aneurysm: Insights from the genetic perspective

This study aims to investigate the genetic link between mental disorders-depression, schizophrenia (SCZ), and bipolar disorder (BIP)-and abdominal aortic aneurysm (AAA).

We first examined the genetic associations between AAA and mental disorders by analyzing global and local genetic correlations as well as shared genomic loci. Global genetic correlation was assessed using linkage disequilibrium score regression (LDSC) and the GeNetic cOVariance Analyzer (GNOVA), while local genetic correlation was analyzed using the SUPERGNOVA approach. To identify shared genetic variants, the pleiotropy-informed conditional and conjunctional false discovery rate (pleioFDR) method was applied. Subsequently, the univariate Mendelian Randomization (UMR) was employed to evaluate the causal relationship, complemented by multivariate MR (MVMR) to account for potential confounding biases. Additionally, mediation analysis was performed to determine whether known risk factors mediate the identified causal relationships.

Global correlations showed positive links between depression, SCZ, and AAA, but not BIP. Local analyses identified specific genomic regions of correlation. We found 26, 141, and 10 shared loci for AAA with depression, SCZ, and BIP, respectively. UMR indicated significant associations between genetically predicted depression (OR 1.270; 95 % CI 1.071-1.504; p = 0.006) and SCZ (OR 1.047; 95 % CI 1.010-1.084; p = 0.011) with AAA, but not BIP. These results were confirmed by MVMR analyses. Mediation analyses showed that smoking, hypertension, hyperlipidemia, and coronary atherosclerosis mediated the impact of depression on AAA while smoking mediated SCZ's impact.

This study provides evidence that genetically predicted depression and SCZ are linked to an increased risk of AAA, mediated by traditional AAA risk factors.