4 research outputs found
Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of HirschsprungÂżs 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.This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, Spain (PI1001290); Spanish Ministry of Economy and Competitiveness (BIO2008-04212), GVA-FEDER (PROMETEO/2010/001) and Consejeria de Innovación Ciencia y Empresa de la Junta de Andalucia (CTS-7447). The CIBER de Enfermedades Raras is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness. LG-A and MVE-R are supported by fellowships PFIS FI10/00020 and FI11/00533 from ISCIII respectively.Peer Reviewe
Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung’s disease
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.Instituto de Salud Carlos IIIMinistry of Economy and Competitiveness, Spain (PI1001290)GVA-FEDER (PROMETEO/2010/001)Consejeria de InnovaciĂłn Ciencia y Empresa de la Junta de Andalucia (CTS-7447