Genetic Complexity of Crohn's Disease in 2 Large Ashkenazi Jewish Families.

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 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 predicted to be deleterious that were observed at a high frequency in cases were prioritized. We undertook within-family association analysis following 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 a 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 replicated in an independent cohort. These findings demonstrate the value of family studies and the importance of the innate immune system in the pathogenesis of CD.