Inflammation Subtypes and Translating Inflammation-Related Genetic Findings in Schizophrenia and Related Psychoses: A Perspective on Pathways for Treatment Stratification and Novel Therapies

Abstract

Dysregulation of immunological and inflammatory processes is frequently observed in psychotic disorders. Numerous studies have examined the complex components of innate and adaptive immune processes in schizophrenia and related psychoses. Elevated inflammation in these conditions is related to neurobiological phenotypes and associated with both genetics and environmental exposures. Recent studies have utilized multivariate cytokine approaches to identify what appears to be a subset of individuals with elevated inflammation. The degree to which these findings represent a general process of dysregulated inflammation or whether there are more refined subtypes remains unclear. Brain-imaging studies have attempted to establish the link between peripheral inflammation and gray matter disruption, white matter abnormalities, and neuropsychological phenotypes. However, the interplay between peripheral inflammation and neuroinflammation, as well as the consequences of this interplay, in the context of psychosis remains unclear and requires further investigation. This Perspectives article reviews the following elements of immune dysregulation and its clinical and therapeutic implications: (1) evidence supporting inflammation and immune dysregulation in schizophrenia and related psychoses; (2) recent advances in approaches to characterizing subgroups of patients with elevated inflammation; (3) relationships between peripheral inflammation and brain-imaging indicators of neuroinflammation; (4) convergence of large-scale genetic findings and peripheral inflammation findings; and (5) therapeutic implications: anti-inflammation interventions leveraging genetic findings for drug discovery and repurposing. We offer perspectives and examples of how multiomics technologies may be useful for constructing and studying immunogenetic signatures. Advancing research in this area will facilitate biomarker discovery, disease subtyping, and the development of etiological treatments for immune dysregulation in psychosis.

Figure 1

Conceptual model of immune dysregulation in psychosis. Converging evidence suggests that genetic and environmental factors increase peripheral inflammation that adversely affects the brain and clinical outcomes. BBB, blood-brain barrier; MHC, major histocompatibility complex.

Figure 2

Functional protein-association network of schizophrenia immune gene and inflammatory biomarker candidates. (A) 41 previously identified schizophrenia immune gene candidates (pink nodes), including 39 non-MHC genes and C4A/C4B, and 13 psychosis-relevant inflammatory biomarkers (maroon nodes) were entered in a protein-protein interaction network analysis using STRING software under default settings with medium confidence (interaction score ≥ 0.4) for identified interactions. The line thickness denotes the strength of data support for a functional interaction between two molecules. (B) MCL clustering of the function network (panel A) to the inflation parameter of 5.0 was performed with clusterMaker and Cytoscape based on the interaction score. Functional interactions within a cluster and between clusters are indicated by thick and thin lines, respectively. MCL, Markov cluster; MHC, major histocompatibility complex.

Figure 3

CNS-specific functional modules for druggable schizophrenia risk genes. The network is comprised of 42 out of 103 druggable genes assigned to one of five clusters (C1–C5) with significant membership. The network clustering was performed based on shared k-nearest-neighbors and community-finding algorithm. Functional enrichment with genes annotated to Gene Ontology Biological Process (GO:BP) terms was examined across five clusters, with the top overrepresented GO:BP terms within each cluster listed on the right (the mapped gene list and full results of pathway enrichment are available in supplemental materials). C2 and C4 containing a total of 17 genes (with polka dots in figure) and 50 enriched terms had strong immune/inflammation implications associated with central nervous system function.