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Correlated expression analysis of genes implicated in schizophrenia: identification of putative disease-related pathways.

ABSTRACT: Schizophrenia (SCZ) is a severe psychiatric disorder affecting 0.7% of the population.[1] When inadequately treated, subjects with SCZ experience symptoms that render them dysfunctional and unable to discern aspects of reality. Despite the fact that the majority of subjects with SCZ are sporadic cases and do not have a known family history of SCZ, a family history is one of the largest risk factors for developing SCZ.[2-4] A large genome-wide association study (GWAS) recently pinpointed 108 significant loci within the human genome that contribute to SCZ pathogenesis.[5] While some loci include genes that have been previously implicated in SCZ, the majority, due to the unbiased nature of the genetic investigation, include genes with unknown relevance to SCZ. This investigation is based on the premise that: 1) at least one of the genes at the 108 loci contribute to SCZ etiology; 2) some of the genes contributing to SCZ etiology are in a common pathway; and 3) some genes in a common pathway will have correlated gene expression. Gene expression data available in the gene expression omnibus (GEO) was used to identify correlated expression among the 369 genes (853 isoforms) found at the 108 loci associated with SCZ. Expression data came from bone marrow CD34+ selected cells isolated from 66 individuals (GSE4619). First, correlation among genes related to the DRD2 pathway was analyzed to test the hypothesis that some SCZ genes are in a common pathway and have correlated expression. Then, two pathways were generated based on correlated expression of genes at the 108 loci. One pathway consisted of the largest number of genes with correlated expression (56) and included four genes from the DRD2 pathway and seven of the 33 genes that were previously implicated in SCZ. The second pathway, a novel pathway of 12 genes, was constructed by excluding both the 33 genes that were previously implicated in SCZ and other genes that exhibited significantly correlated expression with these 33 genes. Correlated expression analysis among SCZ-associated genes at the 108 loci provides evidence implicating those genes with correlated expression in SCZ pathogenesis. In addition, these analyses will facilitate pathway identification creating starting points for targeted experiments to verify or refute the hypothetical pathways generated here. Ultimately identifying the genes and pathways at the 108 loci involved in SCZ genesis will inform novel pharmaceutical development for treatment and prevention of SCZ.

SUBMITTER: Liedtke EI

PROVIDER: S-EPMC7454191 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Correlated expression analysis of genes implicated in schizophrenia: identification of putative disease-related pathways.

Liedtke Erin I EI Zhang Sirey S Thompson John A JA Sillau Stefan S Gault Judith J

New horizons in translational medicine 20161210 5

Schizophrenia (SCZ) is a severe psychiatric disorder affecting 0.7% of the population.[1] When inadequately treated, subjects with SCZ experience symptoms that render them dysfunctional and unable to discern aspects of reality. Despite the fact that the majority of subjects with SCZ are sporadic cases and do not have a known family history of SCZ, a family history is one of the largest risk factors for developing SCZ.[2-4] A large genome-wide association study (GWAS) recently pinpointed 108 sign ...[more]

PMID: 32864408

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Project description:BackgroundIntermediate filament proteins that construct the nuclear lamina of a cell include the Lamin A/C proteins encoded by the LMNA gene, and are implicated in fundamental processes such as nuclear structure, gene expression, and signal transduction. LMNA mutations predominantly affect mesoderm-derived cell lineages in diseases collectively termed as laminopathies that include dilated cardiomyopathy with conduction defects, different forms of muscular dystrophies, and premature aging syndromes as Hutchinson-Gilford Progeria Syndrome. At present, our understanding of the molecular mechanisms regulating tissue-specific manifestations of laminopathies are still limited.MethodsTo gain deeper insight into the molecular mechanism of a novel LMNA splice-site mutation (c.357-2A > G) in an affected family with cardiac disease, we conducted deep RNA sequencing and pathway analysis for nine fibroblast samples obtained from three patients with cardiomyopathy, three unaffected family members, and three unrelated, unaffected individuals. We validated our findings by quantitative PCR and protein studies.ResultsWe identified eight significantly differentially expressed genes between the mutant and non-mutant fibroblasts, that included downregulated insulin growth factor binding factor protein 5 (IGFBP5) in patient samples. Pathway analysis showed involvement of the ERK/MAPK signaling pathway consistent with previous studies. We found no significant differences in gene expression for Lamin A/C and B-type lamins between the groups. In mutant fibroblasts, RNA-seq confirmed that only the LMNA wild type allele predominately was expressed, and Western Blot showed normal Lamin A/C protein levels.ConclusionsIGFBP5 may contribute in maintaining signaling pathway homeostasis, which may lead to the absence of notable molecular and structural abnormalities in unaffected tissues such as fibroblasts. Compensatory mechanisms from other nuclear membrane proteins were not found. Our results also demonstrate that only one copy of the wild type allele is sufficient for normal levels of Lamin A/C protein to maintain physiological function in an unaffected cell type. This suggests that affected cell types such as cardiac tissues may be more sensitive to haploinsufficiency of Lamin A/C. These results provide insight into the molecular mechanism of disease with a possible explanation for the tissue specificity of LMNA-related dilated cardiomyopathy.

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Correlated expression analysis of genes implicated in schizophrenia: identification of putative disease-related pathways.

Publications

Correlated expression analysis of genes implicated in schizophrenia: identification of putative disease-related pathways.

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