title: Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease.
abstract: Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung's disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
authors.forename: Raquel Ma
authors.initials: RM
authors.lastname: Fernández
authors.forename: Marta
authors.initials: M
authors.lastname: Bleda
authors.forename: Rocío
authors.initials: R
authors.lastname: Núñez-Torres
authors.forename: Ignacio
authors.initials: I
authors.lastname: Medina
authors.forename: Berta
authors.initials: B
authors.lastname: Luzón-Toro
authors.forename: Luz
authors.initials: L
authors.lastname: García-Alonso
authors.forename: Ana
authors.initials: A
authors.lastname: Torroglosa
authors.forename: Martina
authors.initials: M
authors.lastname: Marbà
authors.forename: Ma Valle
authors.initials: MV
authors.lastname: Enguix-Riego
authors.forename: David
authors.initials: D
authors.lastname: Montaner
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
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; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male