Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function

Chen, Luo; Pi, Xuenan; Hu, Na; Wang, Xiao; Xiao, Yuan; Li, Siyi; Sweeney, John A.; Bishop, Jeffrey R.; Gong, Qiyong; Xie, Dan; Lui, Su

doi:10.1038/s41380-021-01308-6

Cited by 30 publications

(16 citation statements)

References 82 publications

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“…Based on the evidence that demonstrates schizophrenics can be consistently separated into two subtypes from the DLPFC transcriptome, we next investigated whether these subtypes correspond to the “low” and “high” inflammation biotypes observed by previous studies using peripheral cytokine expression [ 9 , 10 , 11 , 12 , 25 , 26 ]. It is important to note that the gene list used to define the Type 1 and Type 2 subgroups only contained 3 inflammatory-related genes ( IFITM2, IFITM3, and TMEM119 ).…”

Section: Discussionmentioning

confidence: 99%

“…In healthy individuals, there are very little neutrophils within in the brain but neutrophil infiltration into the CNS is a well-documented phenomenon in various pathologies (e.g., infection, trauma, neurodegeneration or autoimmune) [ 39 , 73 , 86 , 87 ]. Previous studies have established links between schizophrenia and increased neutrophil counts in the periphery providing preliminary evidence that neutrophils may also be infiltrating the brain [ 25 , 88 ]. The transmigration of neutrophils to the brain has been linked to the depression-like behaviors and memory deficits during severe systemic inflammation [ 87 , 89 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have provided evidence that inflammation and the immune system may play a role in the schizophrenia pathophysiology (e.g., [ 20 , 21 , 22 , 23 , 24 ]). Building on that, multiple research groups have identified a “high inflammation” or “immuno-subtype” where a subset of schizophrenics show upregulated expressed in immune or inflammation related genes [ 7 , 9 , 10 , 11 , 12 , 25 , 26 ]. A majority of these studies use peripheral blood markers to separate schizophrenics into “high inflammatory” and “low inflammatory” before investigating gene expression [ 9 , 10 , 11 , 12 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Immune-Related Genomic Schizophrenic Subtyping Identified in DLPFC Transcriptome

Childers

Bowen

Rhodes

et al. 2022

Genes

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Well-documented evidence of the physiologic, genetic, and behavioral heterogeneity of schizophrenia suggests that diagnostic subtyping may clarify the underlying pathobiology of the disorder. Recent studies have demonstrated that increased inflammation may be a prominent feature of a subset of schizophrenics. However, these findings are inconsistent, possibly due to evaluating schizophrenics as a single group. In this study, we segregated schizophrenic patients into two groups (“Type 1”, “Type 2”) by their gene expression in the dorsolateral prefrontal cortex and explored biological differences between the subgroups. The study included post-mortem tissue samples that were sequenced in multiple, publicly available gene datasets using different sequencing methods. To evaluate the role of inflammation, the expression of genes in multiple components of neuroinflammation were examined: complement cascade activation, glial cell activation, pro-inflammatory mediator secretion, blood–brain barrier (BBB) breakdown, chemokine production and peripheral immune cell infiltration. The Type 2 schizophrenics showed widespread abnormal gene expression across all the neuroinflammation components that was not observed in Type 1 schizophrenics. Our results demonstrate the importance of separating schizophrenic patients into their molecularly defined subgroups and provide supporting evidence for the involvement of the immune-related pathways in a schizophrenic subset.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immune-Related Genomic Schizophrenic Subtyping Identified in DLPFC Transcriptome

Childers

Bowen

Rhodes

et al. 2022

Genes

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“…In this case, the addition of the HERV-W biomarker aided in the identification of inflammatory subgroups specific to the psychotic disorders. A recent study by Luo et al [ 69 ] clustered schizophrenia patients by their epigenetic profile and identified two subgroups that differed in leucocyte cell counts and neuroanatomical features. Similar subgroups were found when repeating the clustering with controls only, however, the control subgroups did not show neuroanatomical differences, demonstrating specificity of the patient clusters to schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Transdiagnostic inflammatory subgroups among psychiatric disorders and their relevance to role functioning: a nested case-control study of the ALSPAC cohort

et al. 2022

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Individuals with psychotic disorders and depressive disorder exhibit altered concentrations of peripheral inflammatory markers. It has been suggested that clinical trials of anti-inflammatory therapies for psychiatric disorders should stratify patients by their inflammatory profile. Hence, we investigated whether different subgroups of individuals exist across psychiatric disorders, based on their inflammatory biomarker signatures. We measured the plasma concentrations of 17 inflammatory markers and receptors in 380 participants with psychotic disorder, depressive disorder or generalised anxiety disorder and 399 controls without psychiatric symptoms from the ALSPAC cohort at age 24. We employed a semi-supervised clustering algorithm, which discriminates multiple clusters of psychiatric disorder cases from controls. The best fit was for a two-cluster model of participants with psychiatric disorders (Adjusted Rand Index (ARI) = 0.52 ± 0.01) based on the inflammatory markers. Permutation analysis indicated the stability of the clustering solution performed better than chance (ARI = 0.43 ± 0.11; p < 0.001), and the clusters explained the inflammatory marker data better than a Gaussian distribution (p = 0.021). Cluster 2 exhibited marked increases in sTNFR1/2, suPAR, sCD93 and sIL-2RA, compared to cluster 1. Participants in the cluster exhibiting higher inflammation were less likely to be in employment, education or training, indicating poorer role functioning. This study found evidence for a novel pattern of inflammatory markers specific to psychiatric disorders and strongly associated with a transdiagnostic measure of illness severity. sTNFR1/2, suPAR, sCD93 and sIL-2RA could be used to stratify clinical trials of anti-inflammatory therapies for psychiatric disorders.

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“…Our results agreed with multiple evidences of dysregulation of the adaptive immunity cells in schizophrenia 28 . Moreover, a recent study identified a subtype of schizophrenia, using multi-omic measures, which exhibited widespread methylation level alterations among genes enriched in immune cell activity, as well as a higher proportion of neutrophils and lower proportion of lymphocytes 29 . This subtype had higher symptom severity and performed worse on cognitive measures, both factors that could be related to higher relapse rates.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic clocks in relapse after a first episode of schizophrenia

Segura

Prohens²,

Mezquida³

et al. 2022

Schizophr

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The main objective of the present study was to investigate the association between several epigenetic clocks, covering different aspects of aging, with schizophrenia relapse evaluated over a 3-year follow-up period in a cohort of ninety-one first-episode schizophrenia patients. Genome-wide DNA methylation was profiled and four epigenetic clocks, including epigenetic clocks of chronological age, mortality and telomere length were calculated. Patients that relapsed during the follow-up showed epigenetic acceleration of the telomere length clock (p = 0.030). Shorter telomere length was associated with cognitive performance (working memory, r = 0.31 p = 0.015; verbal fluency, r = 0.28 p = 0.028), but no direct effect of cognitive function or symptom severity on relapse was detected. The results of the present study suggest that epigenetic age acceleration could be involved in the clinical course of schizophrenia and could be a useful marker of relapse when measured in remission stages.

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Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function

Cited by 30 publications

References 82 publications

Immune-Related Genomic Schizophrenic Subtyping Identified in DLPFC Transcriptome

Immune-Related Genomic Schizophrenic Subtyping Identified in DLPFC Transcriptome

Transdiagnostic inflammatory subgroups among psychiatric disorders and their relevance to role functioning: a nested case-control study of the ALSPAC cohort

Epigenetic clocks in relapse after a first episode of schizophrenia

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