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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\u2019s 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,<jats:italic>RASGEF1A<\/jats:italic>,<jats:italic>IQGAP2<\/jats:italic>,<jats:italic>DLC1<\/jats:italic>and<jats:italic>CHRNA7<\/jats:italic>, 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.<\/jats:p>","DOI":"10.1186\/1750-1172-7-103","type":"journal-article","created":{"date-parts":[[2012,12,28]],"date-time":"2012-12-28T07:14:14Z","timestamp":1356678854000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung\u2019s disease"],"prefix":"10.1186","volume":"7","author":[{"given":"Raquel Ma","family":"Fern\u00e1ndez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Bleda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roc\u00edo","family":"N\u00fa\u00f1ez-Torres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Medina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berta","family":"Luz\u00f3n-Toro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luz","family":"Garc\u00eda-Alonso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Torroglosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Marb\u00e0","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma Valle","family":"Enguix-Riego","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Montaner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillermo","family":"Anti\u00f1olo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaqu\u00edn","family":"Dopazo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salud","family":"Borrego","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2012,12,28]]},"reference":[{"key":"514_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/jmg.2007.053959","volume":"45","author":"J Amiel","year":"2008","unstructured":"Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, et al: Hirschsprung disease, associated syndromes and genetics: a review. 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