A Putative Causal Atlas of Psychiatric Disorders and Social-Behavioral Traits: A Mendelian Randomization Study

Methods

We implemented bidirectional two-sample MR using summary statistics from large-scale genome-wide association studies (GWAS) to systematically evaluate 3,360 potential causal relationships. The inverse-variance weighted (IVW) method was supplemented by multiple sensitivity analyses.Results: We identified 391 significant causal associations (FDR < 0.05) and confirmed several biologically plausible two-step causal pathways.

For example, adventurousness increases the risk of bipolar disorder by promoting cannabis use (proportion mediated = 4.7%). The effect of narcissistic traits on bipolar disorder is mediated by smoking (46.8%), which is potentially indirectly associated with schizophrenia risk via reduced lung function (47.10%). Neuroticism is a prominent upstream risk factor for major depressive disorder (OR = 2.54, p_FDR = 5.36×10-68).

We also confirmed significant adverse effects of psychiatric disorders on social outcomes such as ADHD reduces the odds of university completion. Sensitivity analyses confirmed that core findings are robust and directionally consistent across methods.Conclusions: By constructing a comprehensive causal atlas of psychiatric disorders and social-behavioral traits using a genetic variable approach, this study elucidates how traits influence psychopathological risk through specific behavioral and particular physiological mediators.

Interventions should integrate psychological, behavioral, and physiological mechanisms to provide a framework for understanding cross-domain causal networks underlying psychiatric disorders.