An encompassing Mendelian randomization study of the causes and consequences of major depressive disorder

Abstract

Major depressive disorder (MDD) is a prevalent and debilitating disorder whose causes and consequences remain insufficiently understood. Genetic variants can be used to study causal relationships with other traits. Here we reviewed 201 MDD-associated traits and performed genetic correlation analyses for 115 traits, two-sample Mendelian randomization for 89 of them, and one-sample Mendelian randomization for an additional 43 outcomes, applying sensitivity tests and power analyses. We show that MDD liability increases risk for poorer circadian, cognitive, diet, medical disease, endocrine, functional, inflammatory, metabolic, mortality, physical activity, reproduction, risk behavior, social, socioeconomic and suicide outcomes. Most associations were bidirectional, although with weaker evidence for diet, disease and endocrine traits causing MDD risk. These findings provide a systematic overview of traits putatively causally linked to MDD—confirming known links and identifying new ones—and underscore MDD as a cross-cutting risk factor across medical, functional and psychosocial domains. The authors analyze genetic correlations and perform Mendelian randomization to reveal bidirectional links between major depressive disorder and various traits, highlighting its role as an important risk factor across medical, functional and psychosocial domains and identifying potential causal relationships.