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

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

doi:10.1007/s00439-018-1927-7

Abstract

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.

Highlights

Crohn’s disease (CD) and ulcerative colitis (UC) are the two major forms of the inflammatory bowel diseases (IBD), a heterogeneous group of chronic and debilitating disorders involving inflammation of the gastrointestinal tract
We recently demonstrated the utility of an Ashkenazi Jewish (AJ) familybased approach for identifying possible causal rare variants for IBD (Levine et al 2016) through the study of the two largest AJ multiplex families described to date (54 and 26 CD cases, respectively)
Variants prioritized from both loci identified by linkage analysis and the family-based rare variant and segregation analyses were examined for evidence of association with IBD (n = 1867), CD (n = 1286) and UC (n = 544) as compared with controls (n = 3035–3616) in an independent cohort of genetically confirmed AJ individuals (Rivas et al 2018)

Summary

Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are the two major forms of the inflammatory bowel diseases (IBD), a heterogeneous group of chronic and debilitating disorders involving inflammation of the gastrointestinal tract. The increased incidence of CD amongst AJs has been genetically interrogated through GWAS (Kenny et al 2012), which highlighted five novel CD-associated loci, and more recently by the analysis of exome sequence data from 1855 AJ CD cases and 3044 AJ non-IBD controls (Rivas et al 2018). AJ CD cases and controls were found to have a greater CD polygenic risk score (incorporating 124 CD risk alleles but not those in NOD2 or LRRK2) compared with non-Jewish European individuals. With a view to further delineating the genetics of IBD, and in particular, to search for high-impact rare variants, we performed whole exome sequencing on a newly established cohort of 960 Jewish individuals from 199 small to medium sized multiplex families with IBD and sporadic cases. Despite the theoretical advantages afforded by studying AJ families, the identification of rare variants for IBD proves challenging

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