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

Schiff ER1, Frampton M1, Ben-Yosef N1,2, Avila BE3,4, Semplici F1, Pontikos N5, Bloom SL6, McCartney SA6, Vega R6, Lovat LB7, Wood E8, Hart A9, Israeli E2, Crespi D10, Furman MA10, Mann S11, Murray CD12, Segal AW1, Levine AP13. Hum Genet. 2018 Aug 22. doi: 10.1007/s00439-018-1927-7. [Epub ahead of print]

Author information

1 Centre for Molecular Medicine, Division of Medicine, University College London, London, UK.

2 Inflammatory Bowel Disease Unit, Institute of Gastroenterology and Liver Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

3 Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.

4 Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

5 UCL Genetics Institute, Division of Biosciences, University College London, London, UK.

6 Department of Gastroenterology, University College London Hospital, London, UK.

7 Research Department of Tissue and Energy, Division of Surgery and Interventional Science, University College London, London, UK.

8 Gastroenterology Department, Homerton University Hospital, London, UK.

9 Gastroenterology Department, St Mark's Hospital, London, UK.

10 Centre for Paediatric Gastroenterology, Royal Free Hospital, London, UK.

11 Gastroenterology Department, Barnet General Hospital, London, UK.

12 Centre for Gastroenterology, Royal Free Hospital, London, UK.

13 Centre for Molecular Medicine, Division of Medicine, University College London, London, UK. a.levine@ucl.ac.uk.


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.

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