title: Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.
abstract: Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.
authors.affiliation: Unit of Animal Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) and Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Momozawa
authors.forename: Myriam
authors.initials: M
authors.lastname: Mni
authors.forename: Kayo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Wouter
authors.initials: W
authors.lastname: Coppieters
authors.forename: Sven
authors.initials: S
authors.lastname: Almer
authors.forename: Leila
authors.initials: L
authors.lastname: Amininejad
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cleynen
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Colombel
authors.forename: Peter
authors.initials: P
authors.lastname: de Rijk
authors.forename: Olivier
authors.initials: O
authors.lastname: Dewit
authors.forename: Yigael
authors.initials: Y
authors.lastname: Finkel
authors.forename: Miquel A
authors.initials: MA
authors.lastname: Gassull
authors.forename: Dirk
authors.initials: D
authors.lastname: Goossens
authors.forename: Debby
authors.initials: D
authors.lastname: Laukens
authors.forename: Marc
authors.initials: M
authors.lastname: Lémann
authors.forename: Cécile
authors.initials: C
authors.lastname: Libioulle
authors.forename: Colm
authors.initials: C
authors.lastname: O'Morain
authors.forename: Catherine
authors.initials: C
authors.lastname: Reenaers
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Curt
authors.initials: C
authors.lastname: Tysk
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hugot
authors.forename: Martine
authors.initials: M
authors.lastname: de Vos
authors.forename: Denis
authors.initials: D
authors.lastname: Franchimont
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Edouard
authors.initials: E
authors.lastname: Louis
authors.forename: Michel
authors.initials: M
authors.lastname: Georges
mesh_terms: D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018123:Receptors, Interleukin / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C515500:IL23R protein, human; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin