title: Discovering genetic variants in Crohn's disease by exploring genomic regions enriched of weak association signals.
abstract: BACKGROUND
  A meta-analysis has re-analysed previous genome-wide association scanning definitively confirming eleven genes and further identifying 21 new loci. However, the identified genes/loci still explain only the minority of genetic predisposition of Crohn's disease.
  
  
  OBJECTIVE
  To identify genes weakly involved in disease predisposition by analysing chromosomal regions enriched of single nucleotide polymorphisms with modest statistical association.
  
  
  METHODS
  We utilized the WTCCC data set evaluating 1748 CD and 2938 controls. The identification of candidate genes/loci was performed by a two-step procedure: first of all chromosomal regions enriched of weak association signals were localized; subsequently, weak signals clustered in gene regions were identified. The statistical significance was assessed by non parametric permutation tests.
  
  
  RESULTS
  The cytoband enrichment analysis highlighted 44 regions (P≤0.05) enriched with single nucleotide polymorphisms significantly associated with the trait including 23 out of 31 previously confirmed and replicated genes. Importantly, we highlight further 20 novel chromosomal regions carrying approximately one hundred genes/loci with modest association. Amongst these we find compelling functional candidate genes such as MAPT, GRB2 and CREM, LCT, and IL12RB2.
  
  
  CONCLUSIONS
  Our study suggests a different statistical perspective to discover genes weakly associated with a given trait, although further confirmatory functional studies are needed.
authors.affiliation: Istituto di Studi sui Sistemi Intelligenti per l'Automazione - C.N.R., Bari, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: D'Addabbo
authors.forename: Orazio
authors.initials: O
authors.lastname: Palmieri
authors.forename: Rosalia
authors.initials: R
authors.lastname: Maglietta
authors.forename: Anna
authors.initials: A
authors.lastname: Latiano
authors.forename: Sayan
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Vito
authors.initials: V
authors.lastname: Annese
authors.forename: Nicola
authors.initials: N
authors.lastname: Ancona
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D003424:Crohn Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions