Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes - PubMed (original) (raw)

Meta-Analysis

Mireia Vilardell et al. BMC Genomics. 2011.

Abstract

Background: Down syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation in the human population and key molecular networks dysregulated in DS are still unknown. Many different experimental techniques have been applied to analyse the effects of dosage imbalance at the molecular and phenotypical level, however, currently no integrative approach exists that attempts to extract the common information.

Results: We have performed a statistical meta-analysis from 45 heterogeneous publicly available DS data sets in order to identify consistent dosage effects from these studies. We identified 324 genes with significant genome-wide dosage effects, including well investigated genes like SOD1, APP, RUNX1 and DYRK1A as well as a large proportion of novel genes (N = 62). Furthermore, we characterized these genes using gene ontology, molecular interactions and promoter sequence analysis. In order to judge relevance of the 324 genes for more general cerebral pathologies we used independent publicly available microarry data from brain studies not related with DS and identified a subset of 79 genes with potential impact for neurocognitive processes. All results have been made available through a web server under http://ds-geneminer.molgen.mpg.de/.

Conclusions: Our study represents a comprehensive integrative analysis of heterogeneous data including genome-wide transcript levels in the domain of trisomy 21. The detected dosage effects build a resource for further studies of DS pathology and the development of new therapies.

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Figures

Figure 1

Figure 1

Characterization of dosage effects. A) Entropy (Y-axis) vs. score of dosage effect (X-axis) for all genes, B) Histogram of scores for all 255 HSA21 genes accessible with the experiments under study, C) Distribution of genomic locations of the 324 candidate genes, D) Cytogenetic location of 77 HSA21 genes that show significant dosage effects for all experiments (blue line). Additionally, the same meta-analysis approach has been conducted with human (green line) and mouse (red line) data separately. The yellow line plots the relative number of HSA21 genes within each band (gene density). Y-axis shows percentage of significant genes with respect to all genes annotated for the chromosomal band.

Figure 2

Figure 2

Molecular interactions of HSA21 genes. A) Interactions of HSA21 genes (red) with non-HSA21 genes (other colours). Same colours of the gene nodes refer to the same chromosome. B) Example of consistent down-regulation of DNAJB1 as a consequence of HSA21 imbalance visualized in the web browser.

Figure 3

Figure 3

Brain-related dosage effects. A) Venn diagram showing the overlap of the 324 significant genes with 623 genes identified by independent mouse studies related to brain phenotypes; B) RNA in situ hybridisations of BACH1 in postnatal mouse embryonic brain slices. C) In situ hybridisation of TTC3 in the same tissue. Images kindly provided by the HSA21 consortium ([4];

http://chr21.molgen.mpg.de/hsa21

). D) Hierarchical clustering of 79 genes related to non-DS general brain disorders with the DS gene expression data sets. Clustering was performed with the J-Express 2009 software using Pearson correlation as similarity measure and complete linkage as update rule.

Figure 4

Figure 4

Novel DS dosage effects visualised with the web browser. A) SST and TAC1 have been previously reported as acting in a complex. The deregulated profile of these genes correlates was shown here with the fold-change view of the web browser. B) HSPA5 is a novel gene for DS implicated in neurodegeneration which is also a target of the ATF6 TF whose target set was enriched with significant genes. The histogram displays the p-values for this gene in individual studies. C) KANK1, a gene previously related with paternally inherited cerebral palsy, shows a consistent trend of up-regulation in the considered studies as shown with the fold-change view of the web browser.

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