title: Pathways systematically associated to Hirschsprung's disease.
abstract: Despite it has been reported that several loci are involved in Hirschsprung's disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung's disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms 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. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Fernández
authors.forename: Marta
authors.initials: M
authors.lastname: Bleda
authors.forename: Berta
authors.initials: B
authors.lastname: Luzón-Toro
authors.forename: Luz
authors.initials: L
authors.lastname: García-Alonso
authors.forename: Stacey
authors.initials: S
authors.lastname: Arnold
authors.forename: Yunia
authors.initials: Y
authors.lastname: Sribudiani
authors.forename: Claude
authors.initials: C
authors.lastname: Besmond
authors.forename: Francesca
authors.initials: F
authors.lastname: Lantieri
authors.forename: Betty
authors.initials: B
authors.lastname: Doan
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Robert Mw
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Av, Manuel Siurot s/n, Seville, 41013, Spain. jdopazo@cipf.es.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006627:Hirschsprung Disease / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics