Journal Article

Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes

Rasche, Axel, Maschke-Dutz, Elisabeth, Vilardell, Mireia, Thormann, Anja, Lehrach, Hans, Herwig, Ralf, Pérez-Jurado, Luis A

2011

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Analysis / Animal Genetics and Genomics / Animals / Brain - metabolism / Chromosomes, Human, Pair 21 - genetics / Complications and side effects / Down syndrome / Down Syndrome - genetics / Down Syndrome - metabolism / Down, Síndrome de / Fenotip / Gene Dosage - genetics / Gene Expression Profiling / Genes / Genetic aspects / Genetic research / Genome, Human - genetics / Genomes / Genomics / Genomics - methods / Gens / Humans / Life Sciences / Medical research / Medicine, Experimental / Mental illness / Mental retardation / Mice / Microarrays / Microbial Genetics and Genomics / Molecular Sequence Annotation / Oligonucleotide Array Sequence Analysis / Patologia / Phenotype / Plant Genetics and Genomics / Proteomics / Research Article / Reverse Transcriptase Polymerase Chain Reaction / Risk factors / Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Transcription Factors - metabolism / Transcription, Genetic