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Psychiatric disorders and neuroticism are closely associated with central nervous system, whose proper functioning depends on efficient protein renewal. This study aims to systematically analyze the association between anxiety / depression / neuroticism and each of the 439 proteins. 47,536 pQTLs of 439 proteins in brain, plasma and cerebrospinal fluid (CSF) were collected from recent genome-wide association study. Polygenic risk scores (PRS) of the 439 proteins were then calculated using the UK Biobank cohort, including 120,729 subjects of neuroticism, 255,354 subjects of anxiety and 316,513 subjects of depression. Pearson correlation analyses were performed to evaluate the correlation between each protein and each of the mental traits by using calculated PRSs as the instrumental variables of protein. In general population, six correlations were identified in plasma and CSF such as plasma protease C1 inhibitor (C1-INH) with neuroticism score (r = - 0.011, P = 2.56 × 10 - 9 ) in plasma, C1-INH with neuroticism score (r = -0.010, P = 3.09 × 10 - 8 ) in CSF, and ERBB1 with self-reported depression (r = - 0.012, P = 4.65 × 10 - 5 ) in CSF. C1-INH and ERBB1 may induce neuroticism and depression by affecting brain function and synaptic development. Gender subgroup analyses found that BST1 was correlated with neuroticism score in male CSF (r = - 0.011, P = 1.80 × 10 - 5 ), while CNTN2 was correlated with depression score in female brain (r = - 0.013, P = 6.43 × 10 - 4 ). BST1 and CNTN2 may be involved in nervous system metabolism and brain health. Six common candidate proteins were associated with all three traits (P < 0.05) and were confirmed in relevant proteomic studies, such as C1-INH in plasma, CNTN2 and MSP in the brain. Our results provide novel clues for revealing the roles of proteins in the development of anxiety, depression and neuroticism., (© 2022. The Author(s).)