Background <p>Psychiatric disorders such as major depressive disorder (MDD), anxiety disorder (ANX), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), and schizophrenia (SCZ) are highly prevalent and often comorbid, contributing significantly to the global disease burden. This study aims to explore the potential causal effects of plasma proteins on these psychiatric conditions and to identify shared proteins that may underlie comorbidities.</p> Methods <p>We conducted two-sample Mendelian randomization (MR) analyses to assess the causal relationships between 2,940 human plasma proteins and six major psychiatric disorders. Sensitivity analyses were performed to confirm the robustness of the findings. We also identified proteins that showed causal effects on multiple disorders.</p> Results <p>A total of eight plasma proteins were identified with causal effects on MDD, twelve on ANX, two on ASD, nine on ADHD, thirty-four on BD, and fifty-two on SCZ. Among these, Mesencephalic astrocyte-derived neurotrophic factor and Otoancorin were associated with both MDD and ANX; von Willebrand factor C domain-containing protein 2-like was linked to both ASD and ADHD; and six proteins—Tumor necrosis factor receptor superfamily member 5, Aspartate aminotransferase, cytoplasmic, Pre-B-cell leukemia transcription factor-interacting protein 1, Hsc70-interacting protein, Serine/threonine-protein kinase 4, and SURP and G-patch domain-containing protein 1—were causally linked to both BD and SCZ.</p> Conclusion <p>This study systematically reveals potential causal associations between plasma proteins and multiple psychiatric disorders and highlights shared proteins potentially involved in the biological mechanisms of comorbidities. These findings offer valuable insights for future research on pathogenesis, biomarker development, and therapeutic strategies in psychiatry.</p>