title: Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping.
abstract: BACKGROUND
  The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.
  
  
  METHODS
  We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.
  
  
  CONCLUSIONS
  The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cutler
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Zwick
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: David T
authors.initials: DT
authors.lastname: Okou
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America; Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Sampath
authors.initials: S
authors.lastname: Prahalad
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walters
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Guthery
authors.affiliation: Icahn School of Medicine, Mount Sinai Hospital, New York, New York, United States of America.
authors.forename: Marla
authors.initials: M
authors.lastname: Dubinsky
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Baldassano
authors.affiliation: Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Wallace V
authors.initials: WV
authors.lastname: Crandall
authors.affiliation: Goryeb Children's Hospital, Morristown, New Jersey, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Rosh
authors.affiliation: Cohen Children's Medical Center, New Hyde Park, New York, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Markowitz
authors.affiliation: Pediatric Gastroenterology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Stephens
authors.affiliation: Baylor College School of Medicine, Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Kellermayer
authors.affiliation: Riley Children's Hospital, Indiannapolis, Indianapolis, United States of America.
authors.forename: Marian
authors.initials: M
authors.lastname: Pfefferkorn
authors.affiliation: University of California, San Francisco, California, United States of America.
authors.forename: Melvin B
authors.initials: MB
authors.lastname: Heyman
authors.affiliation: Hasbro Children's Hospital, Providence, Rhode Island, United States of America.
authors.forename: Neal
authors.initials: N
authors.lastname: LeLeiko
authors.affiliation: Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Mack
authors.affiliation: Vanderbilt Children's Hospital, Nashville, Tennessee, United States of America.
authors.forename: Dedrick
authors.initials: D
authors.lastname: Moulton
authors.affiliation: University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kappelman
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Archana
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Jarod
authors.initials: J
authors.lastname: Prince
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Promita
authors.initials: P
authors.lastname: Bose
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Kajari
authors.initials: K
authors.lastname: Mondal
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Ramachandran
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: John F
authors.initials: JF
authors.lastname: Bohnsack
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Griffiths
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Yael
authors.initials: Y
authors.lastname: Haberman
authors.affiliation: Children's Hospital of Boston, Boston, Massachusetts, United States of America.
authors.forename: Jonah
authors.initials: J
authors.lastname: Essers
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.affiliation: Children Hospital of Pittsburgh, Pittsburg, Pennsylvania, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Keljo
authors.affiliation: Connecticut Children's Medical Center, Hartford, Connecticut, United States of America.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Hyams
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America; Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001483:Base Sequence; D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C515500:IL23R protein, human; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin