Identifying novel proteins underlying schizophrenia via integrating pQTLs of the plasma, CSF, and brain with GWAS summary data

Abstract

Background: Schizophrenia (SCZ) is a chronic and severe mental illness with no cure so far. Mendelian randomization (MR) is a genetic method widely used to explore etiologies of complex traits. In the current study, we aimed to identify novel proteins underlying SCZ with a systematic analytical approach.

Methods: We integrated protein quantitative trait loci (pQTLs) of the brain, cerebrospinal fluid (CSF), and plasma with the latest and largest SCZ genome-wide association study (GWAS) via a systematic analytical framework, including two-sample MR analysis, Steiger filtering analysis, and Bayesian colocalization analysis.

Results: The genetically determined protein level of C4A/C4B (OR = 0.70, p = 1.66E-07) in the brain and ACP5 (OR = 0.42, p = 3.73E-05), CNTN2 (OR = 0.62, p = 2.57E-04), and PLA2G7 (OR = 0.71, p = 1.48E-04) in the CSF was associated with a lower risk of SCZ, while the genetically determined protein level of TIE1 (OR = 3.46, p = 4.76E-05), BCL6 (OR = 3.63, p = 1.59E-07), and MICB (OR = 4.49, p = 2.31E-11) in the CSF were associated with an increased risk for SCZ. Pathway enrichment analysis indicated that genetically determined proteins suggestively associated with SCZ were enriched in the biological process of the immune response.

Conclusion: In conclusion, we identified one protein in the brain and six proteins in the CSF that showed supporting evidence of being potentially associated with SCZ, which could provide insights into future mechanistic studies to find new treatments for the disease. Our results also supported the important role of neuroinflammation in the pathogenesis of SCZ.

Keywords: Complement 4; Mendelian randomization; Neuroinflammation; Protein quantitative trait loci; Schizophrenia.

Fig. 1

Flowchart of the study. We integrated pQTL data derived from brain, CSF, and plasma and SCZ GWAS datasets via MR, Steiger filtering analysis, and Bayesian colocalization analysis. Then, we compared the consistency and differences among the three different tissues and further mapped the interaction networks between the identified proteins

Fig. 2

MR results for pQTLs and SCZ. A Brain pQTL and SCZ. B CSF pQTL and SCZ. C Plasma pQTL and SCZ. The dots colored in blue or red represent the genes that passed the Bonferroni-corrected p-value thresholds (P < 0.05/number of analyzed genes). D Venn plot of the top significant proteins shared by brain, CSF, and plasma pQTLs; the boldly labeled genes indicated those have evidence of colocalization. E Correlation of MR effect between the plasma and CSF (P-value threshold < 0.05)

Fig. 3

Protein-protein interaction. A Protein-protein interaction network between significant schizophrenia-related proteins (P passed the multiple testing) from the brain, CSF, and plasma. B Protein-protein interaction network between suggestive schizophrenia-related proteins(P < 0.05) from the brain, CSF, and plasma. Pink labeled: brain protein; blue labeled: CSF protein; green labeled: plasma protein