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

dc.contributor.authorRivas, M. A. [et al]en
dc.contributor.authorHeap, Grahamen
dc.contributor.authorAhmad, Tariqen
dc.description.abstractAs 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, also available in gnomAD at 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, 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 to pinpoint genetic variation that contributes to variable disease predisposition across populations.en
dc.description.noteThis article is freely available under Open Access. Click on the additional link above to access the full-text via the publisher's site.en
dc.identifier.citationInsights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. 2018, 14 (5):e1007329 PLoS Genet.en
dc.identifier.journalPLoS geneticsen
dc.rightsArchived with thanks to PLoS genetics. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectWessex Classification Subject Headings::Gastroenterologyen
dc.subject.meshCrohn Disease
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshGenetics, Population
dc.subject.meshGenome-Wide Association Study
dc.subject.meshModels, Genetic
dc.subject.meshMolecular Epidemiology
dc.subject.meshPolymorphism, Single Nucleotide
dc.subject.meshRare Diseases
dc.titleInsights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.en
dc.typeJournal Articleen
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Rivas_PLoS Genetics.pdf
2.26 MB
Adobe Portable Document Format
Open Access article
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
1.92 KB
Item-specific license agreed upon to submission