Major depressive disorder and aneurysm: A genetic study of association and causality

Background: Association between depression and aneurysm has been implicated but the specific role of depression in aneurysm remains unclear. We aimed to comprehensively characterize the relation of major depressive disorder (MDD) with aneurysm by subtype. Methods: Harnessing summary statistics from genome-wide association studies (Ncase/Ncontrol = 7603/317,899 for aortic aneurysm; 7321/317,899 for thoracic aortic aneurysm; 3201/317,899 for abdominal aortic aneurysm; 1788/317,899 for cerebral aneurysm; and 246,363/561,190 for major depressive disorder), we estimated the genetic correlation between MDD and each of four aneurysm subtypes via LD Score Regression and tested the causality via various estimators under the bi-directional Mendelian randomization (MR) framework. Results: Positive genetic correlation of statistical significance, ranging between 0.15 (with thoracic aortic aneurysm, P = 0.005) and 0.25 (with abdominal aortic aneurysm, P = 0.001), was consistently observed for MDD with each aneurysm subtype. In the MR analysis of MDD as an exposure, genetic liability to MDD causally increased the risk of cerebral (odds ratio: 1.71; 95 % confidence interval: 1.26-2.34) but not aortic aneurysm. Replication analysis of an independent dataset (Ncase/Ncontrol = 6242/59,418) corroborated this signal. In contrast, causal effect was not evident for any neurysm subtype on susceptibility to MDD. Limitations: Aneurysm could have been underdiagnosed if asymptomatic, leading to an underestimated causal impact on MDD. Non-linearity of the causal effect was not tested due to the lack of individual-level data. Conclusions: Depression and aneurysm may share common pathomechanisms. Screening depressed population and improving the clinical management for depression may benefit the primary prevention of cerebral aneurysm.