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Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder.

Witt SH, Juraeva D, Sticht C, Strohmaier J, Meier S, Treutlein J, Dukal H, Frank J, Lang M, Deuschle M, Schulze TG, Degenhardt F, Mattheisen M, Brors B, Cichon S, Nöthen MM, Witt CC, Rietschel M - Transl Psychiatry (2014)

Bottom Line: In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 × 10(-4)) after adjustment for multiple testing.The present findings suggest that STAB1 is a new and highly promising candidate gene in this region.The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

ABSTRACT
Bipolar disorder (BD) is a highly heritable psychiatric disease characterized by recurrent episodes of mania and depression. To identify new BD genes and pathways, the present study employed a three-step approach. First, gene-expression profiles of BD patients were assessed during both a manic and an euthymic phase. These profiles were compared intra-individually and with the gene-expression profiles of controls. Second, those differentially expressed genes that were considered potential trait markers of BD were validated using data from the Psychiatric Genomics Consortiums' genome-wide association study (GWAS) of BD. Third, the implicated molecular mechanisms were investigated using pathway analytical methods. In the present patients, this novel approach identified: (i) sets of differentially expressed genes specific to mania and euthymia; and (ii) a set of differentially expressed genes that were common to both mood states. In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 × 10(-4)) after adjustment for multiple testing. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.

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Mania associated KEGG pathways clustered on the basis of implicated genes. C1, Cluster 1; C2, Cluster 2; C3, Cluster 3.
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fig2: Mania associated KEGG pathways clustered on the basis of implicated genes. C1, Cluster 1; C2, Cluster 2; C3, Cluster 3.

Mentions: Analysis of KEGG pathways was performed for both the BD euthymic versus control and the BD manic versus control comparison groups. After correction for multiple testing, no pathway had a significant P-value in the BD euthymic versus control analysis. In contrast, the BD manic versus control analysis yielded nine significant pathways (Table 3). Clustering of significant pathways on the basis of gene-content similarity generated three pathway clusters (Figure 2). Cluster 1 consisted of pathways classified as being involved in human diseases, cluster 2 consisted of metabolism pathways and cluster 3 contained the ribosome pathway from the class of KEGG pathways with involvement in genetic information processing. Owing to the small number of dysregulated genes, pathway analyses were not possible for the BD manic versus euthymic comparison.


Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder.

Witt SH, Juraeva D, Sticht C, Strohmaier J, Meier S, Treutlein J, Dukal H, Frank J, Lang M, Deuschle M, Schulze TG, Degenhardt F, Mattheisen M, Brors B, Cichon S, Nöthen MM, Witt CC, Rietschel M - Transl Psychiatry (2014)

Mania associated KEGG pathways clustered on the basis of implicated genes. C1, Cluster 1; C2, Cluster 2; C3, Cluster 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150244&req=5

fig2: Mania associated KEGG pathways clustered on the basis of implicated genes. C1, Cluster 1; C2, Cluster 2; C3, Cluster 3.
Mentions: Analysis of KEGG pathways was performed for both the BD euthymic versus control and the BD manic versus control comparison groups. After correction for multiple testing, no pathway had a significant P-value in the BD euthymic versus control analysis. In contrast, the BD manic versus control analysis yielded nine significant pathways (Table 3). Clustering of significant pathways on the basis of gene-content similarity generated three pathway clusters (Figure 2). Cluster 1 consisted of pathways classified as being involved in human diseases, cluster 2 consisted of metabolism pathways and cluster 3 contained the ribosome pathway from the class of KEGG pathways with involvement in genetic information processing. Owing to the small number of dysregulated genes, pathway analyses were not possible for the BD manic versus euthymic comparison.

Bottom Line: In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 × 10(-4)) after adjustment for multiple testing.The present findings suggest that STAB1 is a new and highly promising candidate gene in this region.The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

ABSTRACT
Bipolar disorder (BD) is a highly heritable psychiatric disease characterized by recurrent episodes of mania and depression. To identify new BD genes and pathways, the present study employed a three-step approach. First, gene-expression profiles of BD patients were assessed during both a manic and an euthymic phase. These profiles were compared intra-individually and with the gene-expression profiles of controls. Second, those differentially expressed genes that were considered potential trait markers of BD were validated using data from the Psychiatric Genomics Consortiums' genome-wide association study (GWAS) of BD. Third, the implicated molecular mechanisms were investigated using pathway analytical methods. In the present patients, this novel approach identified: (i) sets of differentially expressed genes specific to mania and euthymia; and (ii) a set of differentially expressed genes that were common to both mood states. In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 × 10(-4)) after adjustment for multiple testing. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.

Show MeSH
Related in: MedlinePlus