title: Genetic Complexity of Crohn's Disease in Two Large Ashkenazi Jewish Families.
abstract: Crohn's disease (CD) is a highly heritable disease that is particularly common in the Ashkenazi Jewish population. We studied 2 large Ashkenazi Jewish families with a high prevalence of CD in an attempt to identify novel genetic risk variants.
  
  
  
  Ashkenazi Jewish patients with CD and a positive family history were recruited from the University College London Hospital. We used genome-wide, single-nucleotide polymorphism data to assess the burden of common CD-associated risk variants and for linkage analysis. Exome sequencing was performed and rare variants that were predicted to be deleterious and were observed at a high frequency in cases were prioritized. We undertook within-family association analysis after imputation and assessed candidate variants for evidence of association with CD in an independent cohort of Ashkenazi Jewish individuals. We examined the effects of a variant in DUOX2 on hydrogen peroxide production in HEK293 cells.
  
  
  
  We identified 2 families (1 with >800 members and 1 with >200 members) containing 54 and 26 cases of CD or colitis, respectively. Both families had a significant enrichment of previously described common CD-associated risk variants. No genome-wide significant linkage was observed. Exome sequencing identified candidate variants, including a missense mutation in DUOX2 that impaired its function and a frameshift mutation in CSF2RB that was associated with CD in an independent cohort of Ashkenazi Jewish individuals.
  
  
  
  In a study of 2 large Ashkenazi Jewish with multiple cases of CD, we found the genetic basis of the disease to be complex, with a role for common and rare genetic variants. We identified a frameshift mutation in CSF2RB that was replicated in an independent cohort. These findings show the value of family studies and the importance of the innate immune system in the pathogenesis of CD.
authors.affiliation: Division of Medicine, University College London (UCL), London, United Kingdom.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Levine
authors.affiliation: UCL Genetics Institute, University College London (UCL), London, United Kingdom.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pontikos
authors.affiliation: Division of Medicine, University College London (UCL), London, United Kingdom.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Schiff
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.affiliation: UCL Genetics Institute, University College London (UCL), London, United Kingdom.
authors.forename: Doug
authors.initials: D
authors.lastname: Speed
authors.affiliation: Department of Surgery and Interventional Science, National Medical Laser Centre, University College London (UCL), London, United Kingdom.
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Lovat
authors.affiliation: Medical Genomics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Helmut
authors.initials: H
authors.lastname: Grasberger
authors.affiliation: UCL Genetics Institute, University College London (UCL), London, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Division of Medicine, University College London (UCL), London, United Kingdom. Electronic address: t.segal@ucl.ac.uk.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Segal
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D003424:Crohn Disease / Q000208:ethnology / Q000235:genetics*; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics*; D000074623:Dual Oxidases; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells / Q000378:metabolism; D006801:Humans; D007585:Jews / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D019255:NADPH Oxidases / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D055815:Young Adult
chemical_list: C115876:CSF2RB protein, human; D053648:Cytokine Receptor Common beta Subunit; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human
keywords: Complex Disease; Inflammatory Bowel Disease; Pedigree; Population Isolate