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Genetic Complexity of Crohn’s Disease in Two Large Ashkenazi Jewish Families

Levine, AP; Pontikos, N; Schiff, ER; Jostins, L; Speed, D; NIDDK Inflammatory Bowel Disease Genetics Consortium, .; Lovat, LB; ... Segal, AW; + view all (2016) Genetic Complexity of Crohn’s Disease in Two Large Ashkenazi Jewish Families. Gastroenterology , 151 (4) pp. 698-709. 10.1053/j.gastro.2016.06.040. Green open access

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Abstract

Background & Aims 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. Methods 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. Results 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. Conclusions 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.

Type: Article
Title: Genetic Complexity of Crohn’s Disease in Two Large Ashkenazi Jewish Families
Open access status: An open access version is available from UCL Discovery
DOI: 10.1053/j.gastro.2016.06.040
Publisher version: http://doi.org/10.1053/j.gastro.2016.06.040
Language: English
Additional information: Copyright © 2017 AGA Institute. All rights reserved. Open Access funded by Medical Research Council. Under a Creative Commons license https://creativecommons.org/licenses/by/4.0/
Keywords: Inflammatory Bowel Disease; Pedigree; Complex Disease; Population Isolate
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Targeted Intervention
URI: https://discovery.ucl.ac.uk/id/eprint/1504107
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