Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease

E. R. Schiff, M. Frampton, N. Ben-Yosef, B. E. Avila, F. Semplici, N. Pontikos, S. L. Bloom, S. A. McCartney, R. Vega, L. B. Lovat, E. Wood, A. Hart, E. Israeli, D. Crespi, M. A. Furman, S. Mann, C. D. Murray, A. W. Segal, A. P. Levine*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Rare variants are thought to contribute to the genetics of inflammatory bowel disease (IBD), which is more common amongst the Ashkenazi Jewish (AJ) population. A family-based approach using exome sequencing of AJ individuals with IBD was employed with a view to identify novel rare genetic variants for this disease. Exome sequencing was performed on 960 Jewish individuals including 513 from 199 multiplex families with up to eight cases. Rare, damaging variants in loci prioritized by linkage analysis and those shared by multiple affected individuals within the same family were identified. Independent evidence of association of each variant with disease was assessed. A number of candidate variants were identified, including in genes involved in the immune system. The ability to achieve statistical significance in independent case/control replication data was limited by power and was only achieved for variants in the well-established Crohn’s disease gene, NOD2. This work demonstrates the challenges of identifying disease-associated rare damaging variants from exome data, even amongst a favorable cohort of familial cases from a genetic isolate. Further research of the prioritized rare candidate variants is required to confirm their association with the disease.

Original languageEnglish
Pages (from-to)723-734
Number of pages12
JournalHuman Genetics
Issue number9
StatePublished - 1 Sep 2018
Externally publishedYes


FundersFunder number
Charles Wolfson Charitable Trust
Helmsley IBD Exomes Program
Medical Research Council
Wolfson Family Charitable Trust


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