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• W4387476687 abstract "Genome-wide association studies (GWASs) have successfully identified hundreds of genetic loci linked to susceptibility for schizophrenia (SCZ); however, the causal genes and underlying pathophysiological mechanisms at these loci are not well elucidated. Mendelian randomization (MR) analysis has emerged as a powerful tool to investigate potential causal relationships between molecular traits and disease phenotypes in GWAS data. In this study, we utilized Two-Sample MR to integrate large-scale plasma protein quantitative trait loci (pQTL) data from the UK Biobank Pharma Proteomics Project (UKB-PPP) with the most robust schizophrenia GWAS available. We leveraged the largest schizophrenia GWAS conducted by the SCZ Working Group of the Psychiatric Genomics Consortium (PGC3), which included 39,910 SCZ cases and 60,558 controls of European ancestry, as the outcome. For the exposure, genetic variants (cis) associated with 1493 plasma protein identified in the large-scale UKB-PPP (N∼34,000), were used. Effects of the plasma proteins on schizophrenia were analyzed using the TwoSampleMR R package. The potential causal impact of each protein on schizophrenia was evaluated using a Wald ratio and horizontal pleiotropy was tested to ensure validity of Mendelian randomization assumptions. We identified 36 plasma protein-to-disease associations that remained significant after applying the Benjamini-Hochberg correction. In addition to replicating several genes previously reported in pQTL studies of SCZ (e.g., BTN3A2, FURIN), our study identified several novel genes revealing new clues to SCZ pathophysiology. For example, DPEP1 and CHAC2 are involved in glutathione metabolism, which regulates cellular protection from oxidative stress. Previous research has shown that individuals with schizophrenia often exhibit abnormal levels of glutathione, potentially reflecting neuroinflammatory processes. Several additional genes (e.g., BTN2A1) implicated immune processes. Of particular interest, we observed a causal relationship between increased levels of CERT1, a ceramide transporter that plays a role in sphingolipid biosynthesis and neural function, and SCZ risk. Intriguingly, gain-of-function missense mutations in CERT1 have previously been associated with intellectual disability, and recent research suggests that activated CERT1 could potentially be targeted with available small chemical inhibitors. These findings shed light potential involvement of several novel genes in schizophrenia and potential role of genes involved in glutathione and immune pathways developing schizophrenia. Identification of novel gene CERT1, further supports the significance of our study, as it not only provides a potential molecular basis for the disorder but also proposes a conceivable pharmaceutical intervention. While our methodology, focused on the plasma proteome, may exclude essential proteins exclusively expressed in the brain, it is important to note that a significant number of shared pQTLs exist across different tissue types. Moreover, our approach offers a remarkable increase in statistical power, surpassing existing brain eQTL and pQTL datasets by an order of magnitude. Finally, identification of circulating plasma proteins associated with schizophrenia may contribute to development of blood-based biomarkers of illness." @default.
• W4387476687 created "2023-10-11" @default.
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• W4387476687 date "2023-10-01" @default.
• W4387476687 modified "2023-10-16" @default.
• W4387476687 title "F85. PROTEOMIC MENDELIAN RANDOMIZATION REVEALS NOVEL MOLECULAR PATHWAYS IN SCHIZOPHRENIA" @default.
• W4387476687 doi "https://doi.org/10.1016/j.euroneuro.2023.08.467" @default.
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