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.

Large-Scale Mendelian Randomization Study Reveals Circulating Blood-based Proteomic Biomarkers for Psychopathology and Cognitive Task Performance

“…The strength of MR association p-values is represented by a blue gradient across data values. The strength of association is further annotated for easy reference, nominally significant p < 0.05 (circle), FDR significant p scz < 1.49 x 10 - 4 , p BIP < 2.07 x 10 - 5 p MDD < 1.55 x 10 9 p CTP < 2 x 10 - 7 (square) and Bonferroni significant p < 7.34 x 10 - 6 (triangle) are annotated accordingly.…”

“…Genomewide association studies (GWAS) represent a high-throughput, comprehensive, and unbiased tool in providing insights into psychopathology; however, in-depth mechanistic insights that contribute to the disorders' pathogenesis might be further elucidated by leveraging additional functional data. The growing utilization of high-throughput proteomics platforms in large-scale genotyped biobanks provides new opportunities to obtain biological insights from GWAS data [7][8][9][10] . Notably, the Mendelian Randomization (MR) approach 11 permits the identification of causal mechanisms, avoiding the potentially confounding effects of environmental exposures while allowing for sample sizes that are orders of magnitude larger than conventional case-control reports.…”

“…For example, a recent study integrated large-scale psychiatric GWAS with genome-wide association study data for various serum biochemical traits, indicating an association between c-reactive protein levels and several psychiatric illnesses 11 . The growing utilization of high-throughput proteomics platforms in large-scale genotyped biobanks provides new opportunities to obtain biological insights from GWAS data [12][13][14][15] . Notably, the Mendelian Randomization (MR) approach 16 permits the identification of causal mechanisms, avoiding the potentially confounding effects of environmental exposures while allowing for sample sizes that are orders of magnitude larger than conventional case-control reports.…”

Dissecting the shared genetic landscape of anxiety, depression, and schizophrenia

“…Cathepsin S also plays a role in regulating the integrity of the blood–brain barrier (BBB), and changes in BBB permeability may affect the entry of immune cells and inflammatory factors into the brain, potentially contributing to the onset of psychiatric disorders [ 72 ]. Recent genetic studies have found potential associations between the CTSS gene and susceptibility to schizophrenia [ 73 ]. However, it's crucial to note that the relationship between CTSS and psychiatric disorders, especially schizophrenia, is complex and multifactorial.…”

Proteomic Changes in the Hippocampus after Repeated Explosive-Driven Blasts

“…Among these proteins, CNTN2, APBA1, and APBA2 acquire a distinct interest due to their observed involvement in various molecular and clinical conditions . In particular, CNTN2 would certainly deserve further investigations since it has been demonstrated to be implicated in various neurodevelopmental processes , and psychiatric conditions, , which could have indeed a major pathogenetic relevance for blast-TBI related syndromes and PTSD in particular.…”