GSE33759   Details

GSE Accession GSE33759
Title Affymetrix SNP array data for short-segment Hirschsprung trios from 5 different populations
Submission Date 11/16/11
Last Update Date 6/5/13
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Experiment Type SNP genotyping by SNP array; Genome variation profiling by SNP array
Contributor Raquel,M,Fernandez; Marta Bleda; Ignacio Medina; Luz Garcia-Alonso; Martina Marba; David Montaner; Joaquín Dopazo; Salud Borrego
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Summary The reduced numbers of patients available in rare diseases is a major obstacle for finding strong gene associations using conventional gene-based association tests. Conversely, approaches based on the study of collective properties of genes provide a more efficient and sensitive statistical framework that can overcome the sample size limitations in the study of rare diseases. Here, we have conducted a genome-wide transmission disequilibrium association test (TDT) of an international cohort of 214 trios of short-segment Hirschsprung's disease, followed by a functional association study by pathway-based analysis (PBA). The study revealed a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. Also, the functional profiles of association obtained for populations of patients from different countries were compared to each other. While gene associations were different at each country population, the main functional associations were identical in all the five country populations. Supporting the observations made with functional analysis, network analysis uncovered sub-networks of interacting proteins collectively associated to the disease with functionalities that account for several well-known Hirschsprung's features. The use of pathway definitions and gene networks in this analysis pointed to significantly overrepresented gene modules, which could not be discovered by using traditional single-locus approaches. The observations made suggest that Hirschsprung's causative genes would be different in each population although the functional roles affected would be identical. These observations also would explain the general observation of the low reproducibility of particular disease genes across populations.
Overall Design DNA derived from peripheral blood was hybridized to Affymetrix GeneChip® 500K mapping arrays. An international cohort of 215 trios (consisting of affected child and their unaffected parents) from 5 different populations was analyzed. The number of trios per population is as follows: 52 trios from Spain, 26 from France, 37 from Italy, 41 from the USA and 58 from the Netherlands.
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