Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population

Abstract

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10–100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10−16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC (sites VCF available via FTP at ftp.broadinstitute.org/pub/ExAC_release/release0.3/) to pinpoint genetic variation that contributes to variable disease predisposition across populations.

Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity

“…To improve the chances of identifying causally related variants, studies were conducted on Ashkenazi Jews (AJ) because this population has a restricted gene pool because it is thought to have arisen from a relatively small number of individuals about 30 generations ago . CD is about four times as common in AJs as in the general population . Two very large families were investigated.…”

The Multifactorial Etiopathogeneses Interplay of Inflammatory Bowel Disease: An Overview

“…The significance of environmental components is also well recognized by a rising trend in the incidence and prevalence of IBD in countries undergoing rapid Westernization [4,16,60]. As mentioned, genetics is observed to play role as observed by the greater prevalence of IBD in Ashkenazim Jews with trace ancestry in northern-European Jewish groups than Sephardic Jewish population [61,62]. Analyzing data materials from 5685 Ashkenazi Jewish exomes, Rivas et al [62] bring forth a systemic analysis of Ashkenazi Jewish enriched protein-coding alleles, which contribute to distinct in genetic risk to IBD of which are transmitted via autosomal recessive inheritance.…”

“…As mentioned, genetics is observed to play role as observed by the greater prevalence of IBD in Ashkenazim Jews with trace ancestry in northern-European Jewish groups than Sephardic Jewish population [61,62]. Analyzing data materials from 5685 Ashkenazi Jewish exomes, Rivas et al [62] bring forth a systemic analysis of Ashkenazi Jewish enriched protein-coding alleles, which contribute to distinct in genetic risk to IBD of which are transmitted via autosomal recessive inheritance. Other similar such genome-wide scan studies are herewith in-depth discussed [63,64].…”

Fine-scale population structure and demographic history of British Pakistanis

“…To investigate this, we searched for variants with significant allele frequency differences between each of the three largest homogeneous Pakistani subgroups (Pathan in Cluster 8, Bains/Rajput-B in Cluster 9, Jatt/Choudhry in Cluster 10) and all individuals in Clusters 1 to 5 and Cluster 7 ( Figure 2). We used three approaches: pcadapt 65 and GEMMA-LMM 66 for outlier detection on the CoreExome genotype data, and a simple Fisher's exact test on variants ascertained with whole-exome sequencing data, following previous work 67 (see Methods). We found 215 significant variants in 140 independent loci (r 2 <0.2) after multiple testing correction on at least one of these tests (Supplementary Figure 21, Supplementary Tables 14 and 15), including a total of forty-eight protein-altering variants.…”