Integrating Plasma Proteome and Polygenic Risk to Uncover Biological Insights into Schizophrenia
Poster No:
471
Submission Type:
Abstract Submission
Authors:
Jujiao Kang1
Institutions:
1Fudan University, Shanghai, Shanghai
First Author:
Introduction:
Schizophrenia (SCZ) is a complex psychiatric disorder affecting approximately 1% of the global population, imposing a significant burden on individuals and families (Whiteford HA et al. 2013). It is highly heritable, with an estimated heritability of 80% (Sullivan, P. F. et al. 2003), and follows a polygenic pattern, involving thousands of genetic variants across the genome (Trubetskoy, V. et al. 2022). These variants influence multiple biological pathways, affecting gene expression, protein function, and cellular processes (Boyle, E. A. et al. 2017, Liu, X. et al. 2019). Polygenic risk scores (PGS) aggregate these genetic effects into a single measure of susceptibility. While PGS show promise for risk stratification and disease prevention (Zhang, J.-P. et al. 2018), the specific molecular mechanisms underlying these effects are not well understood. Identifying key proteins that integrate these genetic influences could provide valuable insights into disease mechanisms and potential therapeutic targets.
Methods:
Using data from the UK Biobank, we investigated the associations between PGS for SCZ and levels of 2,920 plasma proteins in a cohort of 30,375 participants. We then examined the relationship between these proteins and neuroimaging data, mental health factors, and biological pathways. Additionally, we compared protein-brain associations with gene expression patterns in the brain and brain changes related to schizophrenia.
Results:
We identified 11 proteins significantly associated with the PGS for SCZ (Fig. 1A). Notably, the leucine-rich repeat-containing protein 37A2 (LRRC37A2), interferon gamma receptor 2 (IFNGR2), and butyrophilin subfamily 3 member A2 (BTN3A2) exhibited the most robust associations (Fig. 1). These associations were consistent across various PGS thresholds. In contrast, proteins such as Beta-1,4-glucuronyltransferase 1 (B4GAT1) and neuronal pentraxin receptor (NPTXR) showed significant associations only at stricter PGS thresholds. Furthermore, both B4GAT1 and NPTXR exhibited decreased levels in schizophrenia patients compared to controls (p < 0.05).
We then explored the associations between these proteins and brain structures. After correcting for multiple comparisons using the false discovery rate (FDR), four proteins showed significant associations with at least one of four global brain structures (Fig. 2). Specifically, we observed strong positive correlations between total gray matter volume and cortical gray matter volume with B4GAT1 and NPTXR levels. Several brain regions, including the left rostral middle frontal gyrus, right superior temporal gyrus, and left middle temporal gyrus, were significantly associated with these protein levels.
The NPTXR gene was predominantly expressed in the brain, and plasma NPTXR levels were found to reflect leakage of the brain's NPTXR protein. Additionally, plasma NPTXR levels were associated with several mental health factors, including mania, cannabis use, tiredness, and irritability.
We then explored the associations between these proteins and brain structures. After correcting for multiple comparisons using the false discovery rate (FDR), four proteins showed significant associations with at least one of four global brain structures (Fig. 2). Specifically, we observed strong positive correlations between total gray matter volume and cortical gray matter volume with B4GAT1 and NPTXR levels. Several brain regions, including the left rostral middle frontal gyrus, right superior temporal gyrus, and left middle temporal gyrus, were significantly associated with these protein levels.
The NPTXR gene was predominantly expressed in the brain, and plasma NPTXR levels were found to reflect leakage of the brain's NPTXR protein. Additionally, plasma NPTXR levels were associated with several mental health factors, including mania, cannabis use, tiredness, and irritability.
·Fig.1 Associations between PRS for SCZ and plasma proteins
·Fig.2 Associations between plasma proteins and brain grey matter volumes.
Conclusions:
In this study, we identified several plasma proteins, including B4GAT1 and NPTXR, that are significantly associated with polygenic risk scores for schizophrenia, highlighting their potential role in the molecular underpinnings of the disorder. Notably, these proteins also exhibited significant associations with brain structure, particularly gray matter volume, suggesting a link between peripheral protein levels and brain morphology. These results point to the potential of plasma proteins as biomarkers for schizophrenia risk and disease progression, offering avenues for further research into targeted therapeutic interventions.
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 1
Genetics:
Genetic Association Studies 2
Transcriptomics
Keywords:
Blood
Schizophrenia
STRUCTURAL MRI
1|2Indicates the priority used for review
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Provide references using APA citation style.
Sullivan, P. F., Kendler, K. S., & Neale, M. C. (2003). Schizophrenia as a complex trait: Evidence from a meta-analysis of twin studies. Archives of General Psychiatry, 60, 1187–1192.
Trubetskoy, V., Pardiñas, A. F., Qi, T., et al. (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature, 604, 502–508.
Boyle, E. A., Li, Y. I., & Pritchard, J. K. (2017). An expanded view of complex traits: From polygenic to omnigenic. Cell, 169, 1177–1186.
Liu, X., Li, Y. I., & Pritchard, J. K. (2019). Trans effects on gene expression can drive omnigenic inheritance. Cell, 177, 1022–1034.e6.
Zhang, J.-P., et al. (2018). Schizophrenia polygenic risk score as a predictor of antipsychotic efficacy in first-episode psychosis. American Journal of Psychiatry, 176(1), 21–28.