Transcriptome sequencing study implicates immune-related genes differentially expressed in schizophrenia: new data and a meta-analysis

Sanders, Alan R.; Drigalenko, Eugene; Duan, Jubao; Moy, Winton; Freda, Jessica; Göring, Harald H.H.; Gejman, Pablo V.

doi:10.1038/tp.2017.47

Cited by 49 publications

(40 citation statements)

References 117 publications

(169 reference statements)

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“…The finding of C4 alleles associated with schizophrenia indicates an important genetic influence on the extent of synaptic pruning, which has been hypothesized to play an important role in schizophrenia development [27]. Recently, an RNA sequencing-based transcriptomic profiling study on lymphoblastoid cell lines from a sample of European ancestry (529 schizophrenia cases and 660 controls) found differential expression in components of the complement system (CR1, CR2, CD55, and C3), though not for C4A [28]. Our study demonstrates the potential of C4 as a biomarker of diagnostic value, as it can be identified and differentiated in easily accessible peripheral tissue.…”

Section: Discussionmentioning

confidence: 99%

X-Aptamer Technology Identifies C4A and ApoB in Blood as Potential Markers for Schizophrenia

et al. 2018

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The field of proteomics is rapidly gaining territory as a promising alternative to genomic approaches in the efforts to unravel the complex molecular mechanisms underlying schizophrenia and other psychiatric disorders. X-aptamer technology has emerged as a novel proteomic approach for high-sensitivity analyses, and we hypothesized that this technology would identify unique molecular signatures in plasma samples from schizophrenia patients (n = 60) compared to controls (n = 20). Using a combinatorial library of X-aptamer beads, we developed a two-color flow cytometer-based approach to identify specific X-aptamers that bound with high specificity to each target group. Based on this, we synthesized two unique X-aptamer sequences, and specific proteins pulled down from the patient and control groups by these X-aptamers were identified by mass spectrometry. We identified two protein biomarkers, complement component C4A and ApoB, upregulated in plasma samples from schizophrenia patients. ELISA validation suggested that the observed differences in C4 levels in patients are likely due to the presence of the illness itself, while ApoB may be a marker of antipsychotic-induced alterations. These studies highlight the utility of the X-aptamer technology in the identification of biomarkers for schizophrenia that will advance our understanding of the pathophysiological mechanisms of this disorder.

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Section: Discussionmentioning

confidence: 99%

X-Aptamer Technology Identifies C4A and ApoB in Blood as Potential Markers for Schizophrenia

et al. 2018

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“…Common SNPs from the PGC2 schizophrenia GWAS, which overlap a predicted motif, were extracted. Further, genes from within 10 kb of a predicted DR5-RARE were sourced from the summary statistics of two published schizophrenia RNAseq studies in the brain and blood (Supplementary Note 5) [17,41].…”

Section: Dr5-rare Analysesmentioning

confidence: 99%

“…These genes were enriched for eight pathways after correction for multiple testing (q < 0.05), several of which are involved in neurodevelopment including axon guidance (P = 5.63 × 10 −4 , q = 0.0257) and neural cell adhesion molecule signalling during neurite outgrowth (P = 2.06 × 10 −3 , q = 0.0449, Supplementary Table 3). This approach was also applied to the differentially expressed genes in a large casecontrol study of schizophrenia in lymphoblastoid cell lines (LCLs), with 151 DR5-RARE proximal genes dysregulated [41]. In this instance, 27 pathways were enriched for predominantly immune-related functions such as Measles (P = 2.391 × 10 −5 , q = 8.01 × 10 −3 ) and MHC (Major Histocompatibility Complex) class II antigen presentation (P = 1.87 × 10 −3 , q = 0.0369, Supplementary Table 4).…”

Section: Retinoid Receptor Binding Sites (Dr5-rare) In Schizophreniamentioning

confidence: 99%

Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype

et al. 2018

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Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We hypothesised that a greater burden of common and rare genomic variation in genes involved with retinoid biogenesis and signalling could be associated with schizophrenia and its cognitive symptoms. Common variants associated with schizophrenia in the largest genome-wide association study were aggregated in retinoid genes and used to formulate a polygenic risk score (PRS Ret ) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRS Ret to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRS Ret , were enriched with rare variation in the retinoic acid receptor beta gene RARB, detected through whole-genome sequencing. RARB rare variant burden was also associated with reduced cerebellar volume in the cases with marked cognitive deficit, and with covariation in grey matter throughout the brain. An excess of rare variation was further observed in schizophrenia in retinoic acid response elements proximal to target genes, which we show are differentially expressed in the disorder in two RNA sequencing datasets. Our results suggest that genomic variation may disrupt retinoid signalling in schizophrenia, with particular significance for cases with severe cognitive impairment.

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“…We compared the genes in SCZ network with dysregulated genes [84][85][86][87] or variants 88 identified in SCZ patients collected from recent literature, because these data have not been collected into the databases of SCZ candidate genes. The brain-specific genes were from Illumina Body Map 89 .…”

Section: Scz Network Validationmentioning

confidence: 99%

Systematic search for schizophrenia pathways sensitive to perturbation by immune activation

Gao

Liang

Ren

et al. 2019

Preprint

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Immune activation has been recently found to play a large part in the development of schizophrenia, but the underlying mechanism remains largely unknown. Here, we report the construction of a high-quality protein interaction network for schizophrenia (SCZ Network) using a "neighborhood walking" approach to searching across human interactome network for disease-related neighborhoods. The spatiotemporal expression pattern of the immune genes in the SCZ Network demonstrates that this disease network is sensitive to the perturbation of immune activation during mid-to late fetal development and adolescence. The immune genes in the network are involved in pathways regulating the formation, structure and function of synapses and neural connections.Using single-cell transcriptome sequencing on the brains of immune-activated mice, we found that immune activation disturbed the SCZ network in the major brain cell types and the dysregulated pathways were also involved in synapse regulation, demonstrating that our "neighborhood walking" approach enables biological discovery in complex disorders. 1 in the selected neighborhoods for removing nodes from the candidate SCZ networks. Using on these optimal cutoffs, we obtained a SCZ Network, which has a seed ratio of 72.3% and contains 3,975 nodes and 92,318 edges, including 869 immune genes (658 known SCZ candidate genes) and 3,106 non-immune genes (2,215 known SCZ candidate genes) ( Fig. 1e, Supplementary Data 4). The high quality SCZ network.The primary purpose of our "neighborhood walking" approach is to extract a high-quality disease network from human interactome by removing false positives of SCZ candidate genes while keeping the true positives and novel candidate genes in the network. Of the 3,437 SCZ candidate genes, 3,265 were mapped on the human interactome ( Fig. 2a). After the "neighborhood walking" process, 2,873 schizophrenia candidate genes and 1,102 novel candidate genes were kept in the SCZ Network (Fig. 1e). In order to verify that the "neighborhood walking" approach has removed false positives and kept true positives, we evaluated the SCZ relevance of the kept genes (genes inside the SCZ Network) and removed genes (genes outside the SCZ Network) using three datasets collected from literature (Supplementary Data 5): (i) dysregulated genes in the brain of schizophrenia patients 39-42 , (ii) variants associated with schizophrenia 43 and (iii) genes with brain-specific expression (Expression Atlas) 44 . Compared to removed genes, the kept genes showed significant enrichment with dysregulated genes in the brains of schizophrenia patients (p = 0.0007 for all kept genes, two-side Fisher's exact tests) ( Fig. 2b, Supplementary Data 5), SCZ-associated variants (p = 5.9827e-98 for all kept genes, p = 7.5082e-07 for kept seeds, p = 0.0183 for kept nonseeds, two-side Fisher's exact tests) ( Fig. 2c, Supplementary Data 5), and brain-specific genes (p = 2.3283e-99 for all kept genes, p = 6.0824e-11 for kept nonseeds, two-side Fisher's exact tests) ( Fig. 2d, Supplementary Dat...

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Transcriptome sequencing study implicates immune-related genes differentially expressed in schizophrenia: new data and a meta-analysis

Cited by 49 publications

References 117 publications

X-Aptamer Technology Identifies C4A and ApoB in Blood as Potential Markers for Schizophrenia

X-Aptamer Technology Identifies C4A and ApoB in Blood as Potential Markers for Schizophrenia

Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype

Systematic search for schizophrenia pathways sensitive to perturbation by immune activation

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