Alternatively Spliced Genes as Biomarkers for Schizophrenia, Bipolar Disorder and Psychosis: A Blood-Based Spliceome-Profiling Exploratory Study - PubMed (original) (raw)

Alternatively Spliced Genes as Biomarkers for Schizophrenia, Bipolar Disorder and Psychosis: A Blood-Based Spliceome-Profiling Exploratory Study

S J Glatt et al. Curr Pharmacogenomics Person Med. 2009 Sep.

Abstract

OBJECTIVE: Transcriptomic biomarkers of psychiatric diseases obtained from a query of peripheral tissues that are clinically accessible (e.g., blood cells instead of post-mortem brain tissue) have substantial practical appeal to discern the molecular subtypes of common complex diseases such as major psychosis. To this end, spliceome-profiling is a new methodological approach that has considerable conceptual relevance for discovery and clinical translation of novel biomarkers for psychiatric illnesses. Advances in microarray technology now allow for improved sensitivity in measuring the transcriptome while simultaneously querying the "exome" (all exons) and "spliceome" (all alternatively spliced variants). The present study aimed to evaluate the feasibility of spliceome-profiling to discern transcriptomic biomarkers of psychosis. METHODS: We measured exome and spliceome expression in peripheral blood mononuclear cells from 13 schizophrenia patients, nine bipolar disorder patients, and eight healthy control subjects. Each diagnostic group was compared to each other, and the combined group of bipolar disorder and schizophrenia patients was also compared to the control group. Furthermore, we compared subjects with a history of psychosis to subjects without such history. RESULTS: After applying Bonferroni corrections for the 21,866 full-length gene transcripts analyzed, we found significant interactions between diagnostic group and exon identity, consistent with group differences in rates or types of alternative splicing. Relative to the control group, 18 genes in the bipolar disorder group, eight genes in the schizophrenia group, and 15 genes in the combined bipolar disorder and schizophrenia group appeared differentially spliced. Importantly, thirty-three genes showed differential splicing patterns between the bipolar disorder and schizophrenia groups. More frequent exon inclusion and/or over-expression was observed in psychosis. Finally, these observations are reconciled with an analysis of the ontologies, the pathways and the protein domains significantly over-represented among the alternatively spliced genes, several of which support prior discoveries. CONCLUSIONS: To our knowledge, this is the first blood-based spliceome-profiling study of schizophrenia and bipolar disorder to be reported. The battery of alternatively spliced genes and exons identified in this discovery-oriented exploratory study, if replicated, may have potential utility to discern the molecular subtypes of psychosis. Spliceome-profiling, as a new methodological approach in transcriptomics, warrants further work to evaluate its utility in personalized medicine. Potentially, this approach could also permit the future development of tissue-sampling methodologies in a form that is more acceptable to patients and thereby allow monitoring of dynamic and time-dependent plasticity in disease severity and response to therapeutic interventions in clinical psychiatry.

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Conflict of interest statement

DUALITY/CONFLICT OF INTERESTS

None declared/applicable.

Figures

Fig. (1)

Fig. (1). Alternative Splicing of PTK2B: BPD vs. CNT

The figure illustrates a prototypical example of differential expression of alternatively spliced gene variants between two groups; in this case, BPD and CNT groups. The illustrated gene, PTK2B, produced the smallest _p_-value (8.19_e_−08) for the interaction of diagnostic group (BPD vs. CNT) and exon ID. The top panel shows the four known splice variants of the gene, while the bottom panel plots the raw microarray expression levels (signal intensities, unadjusted for covariates) of individual exons in the BPD and CNT groups (red triangles and blue squares, respectively). The lines representing signal intensity in each diagnostic group closely correspond to each other over most of the length of the gene, but intensities of some exons appeared to diverge, especially in the area of two known splicing sites. When controlling for all covariates, this divergence was statistically significant (*) at exons 2 (_p_=0.010), 31 (_p_=0.007), and 33(_p_=0.027), while the apparent decrease in expression of exon 29 (a known alternatively spliced exon) in the BPD group was not significant (_p_=0.299).

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